Topical drug delivery strategies for enhancing drug effectiveness by skin barriers, drug delivery systems and individualized dosing

Topical drug delivery is widely used in various diseases because of the advantages of not passing through the gastrointestinal tract, avoiding gastrointestinal irritation and hepatic first-pass effect, and reaching the lesion directly to reduce unnecessary adverse reactions. The skin helps the organism to defend itself against a huge majority of external aggressions and is one of the most important lines of defense of the body. However, the skin’s strong barrier ability is also a huge obstacle to the effectiveness of topical medications. Allowing the bioactive, composition in a drug to pass through the stratum corneum barrier as needed to reach the target site is the most essential need for the bioactive, composition to exert its therapeutic effect. The state of the skin barrier, the choice of delivery system for the bioactive, composition, and individualized disease detection and dosing planning influence the effectiveness of topical medications. Nowadays, enhancing transdermal absorption of topically applied drugs is the hottest research area. However, enhancing transdermal absorption of drugs is not the first choice to improve the effectiveness of all drugs. Excessive transdermal absorption enhances topical drug accumulation at non-target sites and the occurrence of adverse reactions. This paper introduces topical drug delivery strategies to improve drug effectiveness from three perspectives: skin barrier, drug delivery system and individualized drug delivery, describes the current status and shortcomings of topical drug research, and provides new directions and ideas for topical drug research.


Introduction
Topical drugs have a long history.Thousands of years ago, ointments and salves made from animal, mineral, or plant extracts were commonly used in Egyptians, Chinese and Babylonians to cure a wide range of ailments (Lima et al., 2021;Metwaly et al., 2021;Roberts et al., 2021).Before 2000 BC, emplastra appeared in China, which maybe the original transdermal patch (Pastore et al., 2015).Many topical drugs are so effective that they are now widely used in many countries, and are also the source of discovery of some very effective monomers.However, there are some topical drugs that seem somewhat incomprehensible nowadays.For example, Kahun gynecological papyrus records that a substance (possibly crocodile excrement) is treated with honey or kefir and injected into the vagina for contraception (Metwaly et al., 2021).During the period of using natural drugs to treat diseases, external medication is one of the most important means of treating diseases.Surviving frescoes and books attest to this (Pastore et al., 2015;Chen, 2016;Zheng and Zheng, 2017).In terms of enhancing the effectiveness of topical drugs, many attempts have been made and many useful results have been achieved.Ancient Egyptians added essential oils to perfumes or ointments to increase the transdermal absorption efficiency of the active ingredients (Elshafie and Camale, 2017); Chinese used wine to soak their medicines to realize the enrichment of the active ingredients and to increase the transdermal absorption efficiency of the active ingredients (Zhu, 2007); and Chinese also heated up topical medicines added with iron sand to be used after application, which is a kind of topical drug formulation design to enhance the therapeutic efficacy of the medicines by heating (Zhu, 2007).In 1860, German chemist Niemann extracted an alkaloid from coca leaves and named it as cocaine.This is the first small molecule topical drug that is generally recognized.In 1884, cocaine was first officially used as a local anesthetic in clinical practice (Grzybowski, 2008).Since then, small molecule drugs have become the overlord of topical drugs to replace natural medicines (Figure 1).
With the continuous development of science and technology and people's deepening of disease understanding, peptides, proteins, nucleic acids, cells and bacteria are gradually used as drugs.The ultimate goal of all topical medication is to reach the target site in vivo with enough dose without side effects.According to the different target sites, topical medication can be divided into four types: 1) Drugs that do not want to be absorbed (e.g., sunscreen, heavy metals); 2) Drugs that reach the skin tissue and do not want to spread (e.g., drugs for the treatment of skin diseases); 3) Drugs that reach deeper tissues (e.g., anesthetics, drugs for treating muscle or joint diseases); 4) Drugs that cross the skin into blood vessels and are transported to other tissues or organs (e.g., insulin).In this paper, diseases are divided into three categories according to different target sites of disease (Table 1).

Properties and functions of four different skin barriers
Recently, our view of the skin has evolved from a mere physical barrier to an organic organ made up of microbial, chemical, physical and immune barriers (Eyerich et al., 2018).Microbial, physical, chemical and immune barriers work synergistically together to maintain homeostasis in the body (Figure 2).
The microbial barrier consists of bacteria, archaea, fungi and viruses which inhabit the surface of the skin and mucous membranes.The microbial barrier can maintain and enhance the skin barrier function through a variety of mechanisms such as competing for nutrients, secreting metabolites, and interfering with the quorum sensing system, inhibiting conditional pathogenic bacterial infection (Uberoi et al., 2021), regulating immunity (Dhariwala and Scharschmidt, 2021), and promoting cell and tissue regeneration (Wang et al., 2023).For example, Staphylococcus epidermidis can affect immune cells in a number of ways thereby promoting neonatal skin barrier development (Severn and Horswill, 2023), enhancing innate immunity and inhibiting invasion by pathogenic bacteria (Gallo, 2015).
Balancing the microbial barrier is key to maintaining healthy skin.Not only can increased abundance of pathogenic bacteria cause or exacerbate disease, but also can non-pathogenic bacteria (Severn and Horswill, 2023).And pathogenic bacteria are not entirely harmful.Under homeostatic conditions, the immune response induced by Staphylococcus aureus colonization of skin tissue can promote the growth of damaged nerve axons and local nerve regeneration (Enamorado et al., 2023).
The physical barrier is made up of the cells that make up the structure of the skin and is divided into epidermis, dermis and subcutaneous tissue.They balance body temperature and moisture, protect the body from ultraviolet exposure, transmit sensations and maintain good health (Eyerich et al., 2018).The stratum corneum is the outermost layer of the epidermis, with a thickness of about 10-20 μm, high density, low water content, low surface area of solute transport, and inactive metabolism, which is figuratively likened to a "brick wall structure" (Yang et al., 2017).The epidermis is mainly composed of keratinocytes with different degrees of differentiation.The keratinocytes move upwards from the basal layer, the degree of differentiation increases, the cells continue to age until they die, and the dead cells eventually accumulate in the outermost layer to form the stratum corneum (Peskoller et al., 2022).The dermis is located below the epidermis, and the basal layer is connected to the dermis layer by means of a basement membrane, which is mainly composed of fibroblasts and plays a supporting role in the epidermis (Ogawa, 2017).Cushioning the epidermis and dermis are layers of subcutaneous tissue and fat that protect the body from damage, provide flexibility and strength, act as a barrier to infection, and act as heat insulation and shock absorption (Singh and Singh, 1993).There are also skin appendages such as hair follicles, sebaceous glands, sweat glands, and nails on the surface of the skin, many of which are directly connected to the dermis and are an important way for drugs, especially macromolecular drugs, to enter the blood.Hair follicles are highly conserved sensory organs that are important reservoirs of keratinocytes and melanocytes in the skin, and hair follicles are also implicated in immune response to pathogens, thermoregulation, sebum production, angiogenesis, neurogenesis and wound healing (Ji et al., 2021).Sebaceous gland is a component of the sebaceous gland unit of the hair follicle, which secretes sebum, and its state is related to hair follicle morphogenesis (Zouboulis et al., 2022).The human body has about 20,000 to 40,000 sweat glands, which are divided into apocrine sweat glands and eccrine sweat glands according to anatomical structure and location (Sato et al., 1989).The end of the exocrine sweat duct is on the surface of the skin, and the end of the apocrine sweat duct is in the hair follicle.
The chemical barrier consists of metabolites from skin cells and microorganisms, and the chemical composition of the barrier varies from site to site, but they all play an important role in maintaining the balance of the skin barrier.The epidermis contains ceramides, free fatty acids, cholesterol, cholesterol sulphates, cholesterol esters and other lipids that are important for maintaining the barrier function of the skin (Starr et al., 2022).The research shows that the skin barrier function is significantly reduced after stratum corneum lipid extraction (Sweeney and Downing, 1970).The main components in sebum are mainly composed of glycerol ester, free fatty acid, cholesterol, Cholesteryl ester, wax ester and marlene.They are skin lubricants and stratum corneum plasticizing lipids, which can maintain the acidic condition of the outer surface of the skin and enhance the skin barrier function, and also play a central role in the composition and functional regulation of the skin microbiome (Qiu et al., 2022;Yin et al., 2023).Dysregulation of sebum secretion is an crucial cause or exacerbation of inflammatory skin disease (Shi et al., 2015).Amino acids, sodium pyrrolidone carboxylate, lactate, urea and other composition with moisturizing functions produced by the disintegration of keratinocytes are called natural moisturizing factors.Natural moisturizing factors are mainly distributed in the stratum corneum, which can regulate the hydration function of keratinocytes, maintain normal skin permeability, and reduce percutaneous water loss of the skin (Mojumdar et al., 2017).The metabolites of microorganisms mainly play a regulatory role.For example, sphingomyelinase can increase ceramide content in the stratum corneum, reduce skin dehydration, and enhance skin barrier integrity (Zheng et al., 2022).Short-chain fatty acids can regulate inflammation and promote wound healing (Stacy and Belkaid, 2019).Sweat glands producing hypotonic solutions can regulation and skin hydration (Roberts et al., 2021).These hypotonic solutions, together with other substances on the surface of the skin, constitute hundreds of components of sweat, and these components can reflect the state of the body (Yang et al., 2023).There is growing evidence that sweat can become a new type of substance to be tested, which can be used to detect diseases or special conditions such as alcohol or drug use.
The immune barrier is an inflammation immune regulatory system composed of various immune cells and inflammatory molecules in the skin.Under normal circumstances, only a small percentage of immune cells reside between the skin tissues.These immune cells residing among skin tissues can respond immediately when the skin is attacked by external forces, such as Langerhans cell and memory cells, which maintain skin stability by secreting antibodies, splitting cells, phagocytosis of pathogens and other means (Kabashima et al., 2019).Microorganisms are an important source for the immune barrier to respond appropriately to stimuli.The moist is an excellent place for microorganisms to communicate with the immune system (Chen et al., 2018).The skin is composed of microorganisms, cells, and the chemicals they secrete.It is an organic whole, and changes in every link can cause skin diseases.The cross-era development of biotechnology has focused research on the single-cell level, and breakthroughs in the analysis of very small samples of nucleic acids, proteins, small molecule compounds and other components have allowed us to deepen our understanding of the occurrence and development of diseases.Cell activity in disease states is summarized here, as detailed in Table 2. Understanding the dynamic changes of different cells in the occurrence and development of diseases is conducive to patients to choose more suitable drugs in different disease states, and improve effectiveness, increase the cure rate of patients, and reduce the pain of patients by actively avoiding drugs with poor effects, or through some measures to improve the efficiency of drugs reaching the target site.Frontiers in Pharmacology frontiersin.org08 Zhao et al. 10.3389/fphar.2023.1333986 3 Drug delivery systems and factors affecting transdermal drug absorption Drug delivery system refers to a technological system that comprehensively regulates the distribution of drugs in an organism in terms of space, time and dose (Baryakova et al., 2023).Ideally, the drug delivery system should allow accumulation of the bioactive composition in the target site at the appropriate dose without overpenetration resulting in the drug reaching the circulation at a toxic dose or accumulating in tissues at non-target sites causing adverse effects (Peralta et al., 2018).Physicochemical properties of drug bioactive composition, excipients and additives, such as molecular weight, partition coefficient, polarity, surface charge and degree of hydrogen bonding, affect the absorption efficiency of drug bioactive composition (Mohammed et al., 2022).Selection of appropriate dosage forms, carriers, additives, and some smart response elements can improve the problems of poor stability, low solubility, and inability to accumulate at the target site of the drug bioactive composition (Figure 3).Garg et al. have given a very detailed account of the commonly used topical dosage forms and additives in their article.So this paper do not cover these two aspects (Garg et al., 2015).

Drug carriers
When the bioactive composition of a drug is poorly stabilized, low solubility, dose-limiting side effects, a narrow therapeutic window or short half-life that makes it difficult to maintain the proper concentration of the drug over a period of time, the choice of the right drug delivery system is an important way to address these issues.Ramanunny et al. described 16 drug delivery systems (Ramanunny et al., 2021).This paper builds on them with a further account of 16 drug carriers (Table 3).

Cell-penetrating peptides
Cell-penetrating peptides, also known as protein translocation structural domains, membrane translocation sequences, or trojan peptides, are small molecules of 6-30 amino acid residues that are able to penetrate biological barriers and cell membranes to enter the cell in a noninvasive manner (Silva et al., 2019).In 1988, Frankel et al. found that the tat protein of human immunodeficiency virus I was taken up into the nucleus by cells grown in tissue cultures (Frankel and Pabo, 1988).Since then, people have begun to take notice of cell-penetrating peptides.Over the course of more than 30 years, the family of cell-penetrating peptides has grown, with more than 100 cell-penetrating peptides described in articles by Milletti alone (Milletti, 2012).Cell-penetrating peptides are classified in a variety of ways.According to their physicochemical properties, cell-penetrating peptides can be simply divided into three categories: cationic, amphipathic and hydrophobic (Raucher and Ryu, 2015).The lack of cell type specificity of cell-penetrating peptides is one of the main reasons preventing their widespread use (Bode Lowik, 2017).The mechanism by which cell-penetrating peptides enter the cell has been the subject of extensive academic interest, but the pathways involved in the process has not been fully elucidated.The mechanisms of cell-penetrating peptide entry into cells identified so far are direct translocation and endocytosis (Guidotti et al., 2017).Cell-penetrating peptide-drug couplers play an important role in the delivery of a wide range of drugs.

Polymer drug delivery systems
Polymers play an important role in drug delivery due to their numerous types, unique three-dimensional structure, high drug loading capacity, and stable physicochemical properties.Polymers have evolved over the past few decades and have appeared in various forms such as hydrogels, polymeric films, and polymeric micelles.Polymers can be categorized into natural and synthetic polymers according to their origin.Natural polymers such as DNA, RNA, and peptides are widely used in bioengineering and drug delivery due to their unique properties (e.g., encodable, biodegradable).With the development of technology, advances in polymer modification techniques and the emergence of 3D printing technology, synthetic polymer carriers are becoming more versatile and powerful.

Hydrogels
Hydrogels are highly porous crosslinked three-dimensional hydrophilic polymer networks of drug carriers that can swell by absorbing large amounts of water (Jindal et al., 2022).The presence of hydrophilic groups such as -CONH 2, CONH-, -OH, -COOH, -SO 3 H, etc., is the main reason why hydrogels can absorb water and swell.In addition to their shared properties, hydrogels have individualized advantages based on their specific material.For example, chitosan and chitin have antimicrobial properties in their own right.So the antimicrobial capacity of gels based on   them is further enhanced (Li et al., 2018).Guanine phosphate can stimulate innate immunity by binding to Toll-like receptor 9, and recognition of DNA hydrogels containing unmethylated cytosinephosphate-guanine dinucleotides further enhances organismal immunity (Nishikawa et al., 2014).Biomaterials such as DNA and proteins, because of their encodable properties and similarity to the organism's microenvironment, can cause some programmed changes in the gel, such as the spontaneous formation of artificial protein scaffolds (Sun et al., 2014).In addition, hydrogel materials can be further enhanced by adding functional groups or incorporating some functional materials to further enhance certain properties.Zhou et al. used a biomimetic mineral plastic of calcium carbonate and polyacrylic acid to give the gel optical properties (Zhou et al., 2020).Haraguchi et al. interwoven polymer and clay into a network to create a hydrogel that can repair itself after damage (Haraguchi et al., 2011).The incorporation of high aspect ratio nanoparticles into suitable gel materials can produce shear-thinning hydrogels, and they can protect cells from high shear forces, leading to a wide range of applications in cartilage tissue regeneration and cell delivery for 3D bioprinting (Thakur et al., 2016).

Microsponges
Microsponges are a new type of drug delivery vehicle of porous polymer microspheres developed in recent years, usually consisting of crosslinked polymers with adsorbent capacity and containing a very large number of porous microspheres ranging from 5 to 300 μm inside, which can adsorb and encapsulate a large number of bioactive composition (Rahman et al., 2022;Tiwari et al., 2022).The microsponges ensure that the drug is localized on the skin surface and within the epidermis and does not diffuse in large quantities to non-diseased areas, preventing toxic effects caused by excessive accumulation of bioactive composition in the epidermis and dermis (Grabow and Jaeger, 2012).Green et al. used bionic microsponges to generate aggregates of inorganic particles that can provide surfaces and structures for cell attachment, organization and promote matrix synthesis (Green et al., 2020).

Polymeric films
Polymer films, which are films made from polymer fibers, have great potential as topical drug carriers.Electrospinning is the fabrication of organized filaments of polymer nanofiber solutions under strong electric field forces, and the resulting fibers have finer diameters (0.1-100 nm) and larger surface areas than those obtained by conventional spinning methods (Bhardwaj and Kundu, 2010).The throughput of nanofibers has become a serious bottleneck limiting their application (Bhardwaj and Kundu, 2010).3D printing is the latest technology for manufacturing polymeric films.3D printing is a technology that uses virtual computer-aided design models to create physical objects by depositing successive layers (Economidou et al., 2018).By 3D printing, it is possible to create polymer films with different porosity, mechanical properties and drug loading to meet the needs of topical drug delivery in different situations.The need for materials with low viscosity, droplet size, lack of precision in positioning, high cost and long production time are factors that limit the widespread use of 3D printing technology for polymer films (Riccio et al., 2022).

Ionic liquids
Ionic liquids are a new type of carrier, and everyone does not define it exactly the same way.Lei et al. considered ionic liquids to be compounds composed entirely of ions with melting points below 100 °C (Lei et al., 2017).Gomes et al. considered ionic liquids as salts formed from organic cations and organic or inorganic anions (Gomes et al., 2021).Unlike conventional salts, it has unique physical and chemical properties.Although the definitions of ionic liquids are not identical, there is no doubt that ionic liquids are liquid salts at ambient temperature.Based on their chemical structure and properties, ionic liquids can be categorized into three groups: water-and air-sensitive ionic liquids, water-and airinsensitive ionic liquids, and biodegradable ionic liquids (Egorova et al., 2017).There are three applications of ionic liquids in increasing transdermal absorption of drugs: 1) Ionic liquids can be used as skin penetration enhancers for pharmaceutical formulations or in combination with other drug carriers.For example, the combination of ionic liquids and gels to form ionic liquid gels has been shown to be very effective in the treatment of infections and haemostasis (Luo et al., 2022;Gao et al., 2023).The mechanism by which ionic liquids promote transdermal absorption of drugs is not well understood, but may be negatively correlated with ionic interactions (Tanner et al., 2019).2) The ionic liquid binds to the drug to form a drug-ionic liquid coupling.The essence of this approach is to convert the drug into a liquid salt so that the drug is characterized by the high stability and solubility of a liquid salt.Moshikur et al. combined 12 hydrophilic drugs with oil-soluble ionic liquids, which significantly increased the transdermal absorption of the drugs and significantly increased the elimination half-life and plasma concentration (Md Moshikur et al., 2022).3) The ionic liquids are constructed by physical or chemical cross-linking to form new drug delivery systems poly-ionic liquids, such as poly-ionic liquid hydrogels.

Deep eutectic solvents
Deep eutectic solvents are novel liquids made by mixing high melting point salts and molecular hydrogen bond donors, which can significantly change the melting point, solubility and biostability of drugs (McDonald et al., 2018).Deep eutectic solvents are usually composed of two or three inexpensive and safe components, which are capable of joining with each other through hydrogen bonding interactions to form low eutectic mixtures, and deep eutectic solvents with a high melting point are also chosen for some thermally unstable drugs to enhance the thermal stability of the drug (Zhang et al., 2012;Kumar and Nanda, 2018).However, how deep eutectic solvents promote transdermal drug absorption has been inconclusive.Boscariol et al. found that choline geranate deep eutectic solvent may have contributed to the penetration of bioactive molecules through the openings by sliding around the fatty compounds that make up the interstitial space between keratinocytes and by creating small transient openings in the cell membrane (Boscariol et al., 2021).However, the resulting small transient openings in the cell membrane did not cause damage to the skin tissue structure.In addition to this deep eutectic solvents can be involved in the stimulation of important components of the response element for precise drug delivery (Shi et al., 2022).Perhaps 1 day we will be able to use deep eutectic solvents to better achieve precise localization and dose control of transdermal drug absorption.

Liquid crystals
Liquid crystals are a state of matter between a solid and a liquid, having both fluidity like a liquid and an orderly arrangement of crystals (Dierking and Al-Zagana, 2017).In 1957, Brown and Shaw described the physical properties of liquid crystals in their book (Mitov, 2017).Liquid crystals can be classified into a number of categories based on the conditions under which the liquid crystal state is maintained.The most commonly used classification of liquid crystals is the division of liquid crystals into thermotropic liquid crystals, which maintain the liquid crystal state within a certain temperature range; and lyotropic liquid crystals, which maintain the liquid crystal phase state under specific concentration conditions.The difficulty in realizing thermotropic liquid crystals at ambient temperature is the reason why almost no thermotropic liquid crystals are used in drug delivery systems.However, it has recently been found that thermotropic liquid crystals can alter the spontaneous water flux at the liquid crystal phase and interface by changing the type and concentration of the added electrolyte, further reorienting the liquid crystals at the aqueous interface and thus releasing the substances stored in the liquid crystals (Ramezani-Dakhel et al., 2017).In this way, thermotropic liquid crystals have the possibility and potential to become drug delivery systems that can precisely control drug release.The liquid crystallinity of lyotropic liquid crystal is a function of concentration and is mostly composed of amphiphilic molecules, the most common types being cubic, hexagonal and layered intermediate phases (Chavda et al., 2022).Many lyotropic liquid crystals have a lipid structure with similarities to the stratum corneum and strong bioadhesive properties, giving them an important place in transdermal drug delivery systems (Lotfy et al., 2022).

Metal-organic frameworks
Metal-organic frameworks are a class of highly ordered crystalline porous coordination polymers formed by the coordination of metal (transition metal or lanthanide metal) ions and organic ligands (carboxylates, azides, and phosphonates) that adsorb functional molecules on external surfaces or in open channels and trap these molecules in the backbone (Sun et al., 2020;Cheng et al., 2022).Metal-organic frameworks are produced by hot-melt, microwave-assisted synthesis, ultrasonic-assisted synthesis, etc.The metal-organic frameworks synthesised by different methods affect their crystal structure, size, porosity and other properties.Metal-organic frameworks can be used in conjunction with the formation of nanomaterials containing the active ingredient of a drug or with stimulus-responsive elements for the fine delivery of localised drugs (Zhao et al., 2019;Pan et al., 2022).

Bacteria and bacterial derivatives
Bacteria and bacterial derivatives, including bacterial ghosts and extracellular vesicles, are very promising bio-nanomaterials.Drug delivery platforms of bacteria and their derivatives retain some of the autonomous and dynamic functions of bacteria, such as colonization and targeting of human tissues, tissue penetration ability and enhanced activation of the body's immune response (Chen et al., 2021).Compared with chemically synthesized drug carriers (nanoparticles and liposomes, etc.), drug carriers composed of natural biomaterials have both active and passive targeting properties (Cao and Liu, 2020).Endowed by means of engineering, bacteria and their derivatives can also be endowed with additional functions (Li et al., 2021).

Bacteria
Bacteria are closely associated with human health and disease development, playing a key role in preventing and maintaining atherosclerosis, fighting skin cancer, promoting skin wound healing and hair follicle rejuvenation, and neurological disorders including depression (Gilbert et al., 2013;Li et al., 2016;Naktsuji et al., 2018;Wang et al., 2021;Qiao et al., 2022).There are two common bacterial drug carriers (Li et al., 2021).One is the integration of diseasetreating genes into the bacterial chromosome by means such as CRISPR-Cas9, which is developed into a living biopharmaceutical, allowing the drug to be continuously produced as the bacteria metabolize.The other is to load the drug into the living bacterial body to release the drug with bacterial lysis.Vishnu et al. studied and developed a non-pathogenic, therapeutic delivery system for Salmonella strains that can efficiently deliver bioactive proteins into cells by utilizing genetic circuits to control protein synthesis, invasion into the cell and release of protein drugs.And it can deliver drugs directly to cancer cells specifically without affecting healthy cells (Raman et al., 2021).The combination of the bacterial carrier effect with its own effects such as enhancing the immune response will certainly lead to better therapeutic results.In the future, the bacterial drug delivery system may be able to deliver drugs as precisely as an intelligent robot.

Bacterial ghosts
Bacterial ghosts are produced by the release of bacterial cytoplasmic contents through channels in the cell envelope, mainly from Gram-negative bacteria.The high number of cell wall layers, strong mechanical properties, the presence of more toxic exotoxins and the absence of a relatively simple protein secretion mechanism and high transporter capacity may be the reasons why Gram-positive bacteria are generally not used as delivery vectors but as vaccines (Hjelm et al., 2015;Wu et al., 2017).There are two methods of creating bacterial ghosts, the chemical-based "sponge-like" method and the geneticallyengineered method, which is prepared by cleavage of gene E. The method is based on the use of chemical reagents.The "sponge-like" method refers to the use of chemicals to create pores through the bacterial cell wall, followed by centrifugation to remove the cell contents (Chen et al., 2021).The genetic engineering method utilizes the cleavage protein E produced by the cleavage gene E to cause the formation of transmembrane tunnels connecting the inner and outer membranes near the bacterial division site, flowing out of the cytoplasm and producing bacterial ghosts with surface structures identical to those on the surface of living cells (Ma et al., 2021).Beyond that, some bacterial ghosts have the ability to target infected macrophages (Xie et al., 2020).Combining bacterial ghosts with micro needling or subcutaneous injections would have great potential for application in bacterial infections of the skin or deep tissues.

Bacterial extracellular vesicles
Bacterial extracellular vesicles are spherical membrane particles with diameters of 20-400 nm secreted by commensal or pathogenic bacteria, which can be categorized into cytoplasmic membrane vesicles and outer membrane vesicles according to the type of bacteria secreted (Liu et al., 2022).Cytoplasmic membrane vesicles are derived from the cytoplasmic membrane of Grampositive bacteria carrying material from the cytoplasm.Outer membrane vesicles are derived from the outer membrane of Gram-negative bacteria carrying material from periplasmic and cytoplasmic components (Toyofuku et al., 2019).Bacterial extracellular vesicles are the language of communication between bacteria and hosts, and can be used to regulate a variety of biological functions including biofilm formation, alteration of small intestinal epithelial permeability (Fizanne et al., 2023), increase in host angiogenesis and osteogenesis (Chen et al., 2022), inhibition of host viral infections and host collaboration in viral clearance (Ñahui Palomino et al., 2019;Bhar et al., 2022), induction of host resistance to other bacteria (Zhou et al., 2023), and host immunomodulation (Xie et al., 2022).Bacterial extracellular vesicles can release the contents of bacterial extracellular vesicles into host cells through three ways: endocytosis, internalization of bacterial extracellular vesicles through lipid rafts, and direct membrane fusion (Ñahui Palomino et al., 2021).Endocytosis is considered to be the main route of entry of bacterial extracellular vesicles into eukaryotic cells.

Cells and cell derivatives
Cells and cell derivatives, including cell membranes and cell vesicles, are drug delivery systems that modify drugs to the surface of cell membranes, encase them inside the living cell membranes, or integrate them onto cellular nucleic acids.When modified cells are delivered into a patient, such as by integrating gene fragments onto nucleic acids or wrapping around the inside of cells, they can become a kind of "living drug", constantly producing drugs as cells metabolize or releasing a certain number of drugs as special events occur.Differences in the composition of their membranes, types of receptors, etc., of cells and cell derivatives of different origins have the ability of active/passive targeting to specific tissues.Some cells and cell derivatives also have the ability to activate the immune system, which can assist drugs to better treat diseases.Cells and cell derivatives have a wide scope for development in precision therapy and as controlled targeted drug carriers.

Cells
A cellular drug carrier is one that utilizes an intact cell or a denucleated cell as a carrier.In contrast to being intact, denuded cells not only do not proliferate or permanently engraft in the host, they also retain organelles to produce energy and proteins.Desmoplastic cells adhere to target cells or tissues through integrin-regulated adhesion and their functional properties are highly similar to those of extracellular vesicles (Wang et al., 2022).Red blood cells are unique in that they are whole cells and do not possess a nucleus of their own, allowing them to be transported to tissues through the bloodstream.Mesenchymal stem cell, with their intrinsic disease-targeting and paracrine capabilities, have gained a great deal of attention as therapeutic vectors.The short lifespan of neutrophils means that drugs can enter the bone marrow as senescent neutrophils return to the bone marrow.In addition, cells such as hematopoietic stem cells, platelets, natural killer cells, macrophages, dendritic cells, T-lymphocytes and tumor cells have also been used as drug delivery vehicles.The combination of these cells with topical implantation techniques or microneedling could have a promising future in the topical treatment of diseases of the skin and subcutaneous tissues.

Extracellular vesicles
Extracellular vesicles are nanoparticles encapsulated by lipid membranes secreted by cells, and are widely distributed in various body fluids, tissue fluids and cell culture supernatants (Hallal et al., 2022).Extracellular vesicles are both a means of disposing of harmful or unwanted intracellular components and are capable of long-range intercellular communication in vivo surface proteins, encapsulated cargo molecules (e.g., biologically bioactive molecules such as proteins, lipids, nucleic acids and sugars) (Shao et al., 2018;Buzas, 2023).Depending on the source, particle size, structure and function, extracellular vesicles can be categorized into various types such as exosomes, microvesicles, apoptotic bodies and oncosomes.The first extracellular vesicles identified were those loaded with transferrin receptors, which were excreted by reticulocytes via exosomes (Harding et al., 1984).With the exploration of extracellular vesicles, the therapeutic potential of extracellular vesicles in various diseases continues to be discovered.

Cell membrane
Cell membrane is a drug carrier in which the cell membrane of a certain cell is wrapped around the outer layer of the drug.Erythrocytes, leukocytes, platelets, cancer cells, macrophages, mesenchymal stromal cells, and exosomes have been used as cell membrane drug carriers.They closely resemble cell membrane components in vivo and carry a large number of surface molecules, possessing similar functions to cells and exosomes.Different types of cell membranes also possess their individualized functions.For example, drugs encapsulated in natural erythrocyte membranes inhibit drug uptake by the reticuloendothelial system (Rao et al., 2016).The membranes of macrophages, leukocytes and monocytes have a high affinity for inflamed and tumor-bearing regions, easily pass biological barriers, and can migrate transendothelially (Narain et al., 2017).The cell membranes of platelets have subendothelial adhesion properties as well as the ability to interact with pathogens (Kunde and Wairkar, 2021).Human keratinocyte membranes can achieve precise targeted release of drugs in the skin, which has a broad application prospect in dermatological treatment and functional cosmetic delivery (Jing et al., 2021).

Inorganic drug carriers
Drug carriers made from organic materials can easily dissolve and encapsulate poorly water-soluble drugs into their hydrophobic cores, but are also physicochemically and chemically unstable, making them susceptible to accidental drug leakage.Drug carriers made from inorganic materials such as mesoporous silica nanoparticles, carbon nanomaterials and gold nanoparticles are highly physicochemically and biochemically stable, less expensive to manufacture, and can provide sufficient attachment sites for a variety of organic components.Many inorganic drug carriers can also be prepared in a variety of sizes, structures and geometries.Compared to some highly biocompatible organic carriers, inorganic carriers are less able to cross the skin barrier, but the high drug loading capacity can be used as a strategy to control the retention and release of therapeutic candidates.

Silicon dioxide
Silicon dioxide drug carriers are drug carriers made of silicon dioxide, first synthesised in the 1990s, and are available in spherical, rod and flake shapes (Vallet-Regí et al., 2022).A type of silica porous microspheres with pore sizes ranging from 2 to 50 nm has occupied an important position in the family of silica drug carriers since its discovery, which is mesoporous silica (Vallet-Regí et al., 2022).In addition to this, many researchers have structurally modified mesoporous silica to give mesoporous silica a richer and more personalized advantage.For example, Xu et al. utilized a chiral amide gel-directed synthesis method that could give mesoporous silica significant chiral activity (Xu et al., 2023).Shiekh et al. modified mesoporous silica with hexamethylsilazane, which avoided agglomeration and was more conducive to targeted delivery (Shiekh et al., 2022).Difficulty in entering the bloodstream through the human stratum corneum even with the addition of chemical penetrating agents is the main obstacle that restricts the use of mesoporous silica drug carriers for some topical drugs.However, Zhao et al. utilized the drag effect of low eutectic solvents to enable mesoporous silica drug carriers to effectively penetrate the entire skin (Zhao et al., 2022).

Calcium carbonate
Calcium carbonate is one of the most widespread minerals found in nature and is also widely found in living organisms as a structural support.Calcium carbonate exists in various forms, such as amorphous and crystalline.There are six known crystalline forms of calcium carbonate, namely, calcite, aragonite, spherulite, calcium carbonate monohydrate, calcium carbonate hexahydrate, and calcium carbonate hemihydrate.The Ca 2+-CO 3 2-reaction system is the most commonly used way to synthesize calcium carbonate.Calcium carbonate with different sizes, morphologies and crystalline forms can be obtained by changing the reaction conditions (Niu et al., 2022).Surface modification is the main method to expand the application of calcium carbonate in drug carriers.Calcium carbonate was further engineered into porous, hollow or core-shell organic-inorganic nanocomposites by organic modification or inorganic modification, followed by templateinduced biomineralization and layer-by-layer assembly of the resulting CaCO 3 (Niu et al., 2022).Dong et al. utilized hollow calcium carbonate-polydopamine composite nanomaterials to fabricate a photosensitizer-loaded drug carrier that could significantly reduce phototoxicity and thus effectively minimize skin damage during in vivo antitumor photodynamic therapy (Dong et al., 2018).

Drug-smart response element
Drug-smart response elements are elements that can be targeted for delivery to a focal site after receiving a specific external or internal stimulus.In contrast to conventional drugs, stimuliresponsive elements can use a variety of principles to respond to subtle changes in the body's environment, thereby delivering the drug precisely to the target site, which can reduce unwanted toxic side effects of the drug at non-target sites without increasing the concentration of the drug (Table 4).

Ligand-mediated of drug-smart response element
Chemical modification has been an important way to improve the performance of drugs or carriers.Ligand-drug couplings are one such chemical modification method that has received widespread attention, first appearing in the 1870s (Chau et al., 2019).Small molecules have since been used as ligands, but antibodies as ligands have been the most dominant research direction.Currently, antibody couplings are developing rapidly.In addition to enhancing the targeting ability of drugs, antibody couplers can also activate the body's immune response and regulate cell behaviour (Qian et al., 2021;Liu et al., 2023).The choice of antibodies is not limited to proteins with direct potency similar to those in the human body, but also includes bacterial surface proteins with indirect potency (Lahav-Mankovski et al., 2020).Some researchers have found that further modification of bacterial antibodies can give bacteria programmable properties to more finely regulate the organism by inducing cellular functions in a manner similar to cell surface protein responses.However, antibody couplings have a poor ability to penetrate barriers, and intravenous injection is the predominant route of administration.The application of microneedling and embedding technologies may be an important step in further expanding the application of ligandmediated drug smart response elements.

pH-responsive drug smart response element
pH-Responsive drug smart response element is a drug delivery system that combines a pH-responsive structure, such as a 3+ carboxylic acid ligand, through surface adsorption, surface modification and mixing (Guillen et al., 2022;Tian et al., 2022).The most commonly used design is the modification of the carboxyl group of a protein with a stilbene analogue, which binds to the biologically active ingredient of a target drug having p-dimethylaminobenzaldehyde or to a drug carrier (Herold et al., 2020).pH-responsive drug smart response elements allow for the slow, sustained release of drugs from the smart response element at varying rates depending on the acidification conditions of the human environment, and have great potential for the long-term sustained release of drugs.In vivo pH-responsive drug smart response elements have major limitations.However, pHresponsive drug smart response elements have great applications in skin bacterial infections and trauma (Xie et al., 2023).

Redox-responsive drug smart response element
Redox-responsive drug-smart response elements typically contain disulfide and diselenide bonds that load the active pharmaceutical ingredient in a covalent or non-covalent manner and release the active pharmaceutical ingredient in response to oxidative stimulation (Li et al., 2022).The most commonly recognized substrates are reactive oxygen species and glutathione.The very slow kinetics of the classical "thiol-disulfide bond exchange reaction" is a major drawback of redox-responsive drug-smart response elements.Relief through the addition of core gating molecules can improve the accuracy of drug release and enable more precise disease targeting (Li et al., 2022).Because bacteria contain high concentrations of glutathione, the redox-responsive drug smart response element is likely to clear the bacteria (Wu et al., 2023).The skin is more prone to artificially modulate drugs, and redox-responsive drug-smart response elements have great potential for skin or mucosal antimicrobials.

Enzyme-responsive drug smart response element
The design principle of enzyme-responsive drug smart response elements is to utilize specific interactions between enzymes and substrates to prepare drug-smart response elements that can be specifically degraded by specific enzymes (Zhou et al., 2022).Precise localisation of enzyme-drug smart response elements could control the drug release dose according to disease severity and greatly reduce cytotoxicity (Zuo et al., 2020;Chen et al., 2021).In addition to this, enzyme-drug smart response elements have some personalized advantages.Self-assembled peptide thioesters consisting of aminoethyl thioesters as substrates for thioesterases can act on the Golgi apparatus of target cells in a timely and efficient manner via an enzymatic reaction, leading to cell death through a variety of pathways (Tan et al., 2022).Enzyme-responsive drug smart response elements can deliver live drugs such as cells and bacteria.Yang et al. solved the problems of low cell survival and severe immune rejection by utilizing matrix metalloproteinase-7responsive nanoshells to encapsulate HeLa cells and human mesenchymal stem cells (Yang et al., 2019).

Magnetically responsive drug smart response element
Magnetic nanoparticles are 10-100 nanoparticles represented by iron, cobalt, nickel or metal oxides with inherent magnetic properties are the main source of magnetically responsive targeted drug delivery systems (Shi et al., 2022).Superparamagnetic magnetic hematite (γ-Fe2O3) or magnetite (Fe 3 O 4 ) are commonly used magnetic nanoparticles in magnetically responsive drug smart response elements.Micro-robotics is the most ideal development direction for magnetically responsive drug smart response elements.An ideal micro-robotic drug smart response element should fulfill four core requirements: 1) high loading capacity, 2) protection of the drug from the external environment, 3) controllable propulsion mechanism, and 4) on-demand drug release (Song et al., 2022).However, achieving the above conditions using magnetically responsive elements is a long way from controlling the micro-robot to deliver the drug to the specified location.

Factors affecting transdermal drug absorption
Permeation of drugs through biological or synthetic membranes occurs through three main modes of transport: passive, active or facile.Transdermal absorption in humans or animals is the passive diffusion of drugs from carriers or excipients on skin surface tissues to reach the systemic circulation (Schaefer et al., 2013).The physiologic structures involved in the transdermal absorption of topical medications are the stratum corneum, hair follicles, sebaceous glands, and sweat duct orifices.The pathways of topical drug penetration through the stratum corneum can be categorized into three: 1) Intercellular pathway: chemicals bypass the keratinocytes and penetrate into the subcutis through the intercellular matrix that is continuously distributed between the keratinocytes (Barbero and Frasch, 2006).This is the main route for bioactive composition in drugs with very small molecular weights to enter the skin.The bioactive components of drugs that enter the skin via the intercellular route are of low molecular weight and have a certain degree of lipid-and water-solubility (David, 2014).2) Transcellular entry: the chemical enters the target site either directly through keratinocytes and mesenchyme or through efflux and uptake transporters using transporters (Haque and Talukder, 2018;Bajza et al., 2020).The bioactive composition with smaller molecular weights directly pass through the cell membrane, while the components with larger molecular weights interact with transport proteins and pass through the cell membrane through efflux and uptake transporters (Idson, 1975).3) The transdermal route by which chemicals enter the dermis directly through skin appendages such as hair follicles, sebaceous glands and sweat duct orifices is also known as the bypass route.In most cases, drug bioactive composition with large molecular weights or peculiar structures have difficulty in passing through the thicker lipid-rich stratum corneum and enter the skin mainly via the bypass route (Stoughton, 1965).The total area of the skin appendages is relatively small, but it has a significant impact on the skin permeability of drug bioactive composition (Marwah et al., 2016).The bypass pathway is an important reason why topical drugs resemble slow-release drugs.The storage of drugs in the skin appendages and the extremely thin stratum corneum of the skin appendages allow large molecular weight drug bioactive composition to cross the skin slowly at a constant rate for a certain period of time to reach the target site (Scheuplein and Blank, 1971;Ishii et al., 2010).
The nature of drug absorption on the skin is a passive diffusion process from the outer part of the skin, where the concentration is high, to the inner regions of the skin, where the concentration is low.In principle, all three pathways follow Fick's law of diffusion, which states that the flux or motion of a molecule diffusing across a membrane is proportional to the difference in concentration of that molecule on either side of the membrane (Idson, 1975).The formula based on Fick's first law of diffusion indicates that the maximum flux of a drug is proportional to the difference in skin concentration and inversely proportional to the thickness of the stratum corneum.Fick's second law of diffusion suggests that the relationship between diffusion distance and the duration until an isopore (an area of the same drug concentration) is reached is not linear, but increases disproportionately with increasing diffusion distance (Wohlrab and Eichner, 2023).However, the efficacy of some drugs decreases significantly with increasing drug concentration (Hemmati et al., 2011), indicating that in addition, there are other important factors that similarly influence drug penetration and absorption.The integrity and properties of the membrane (skin) as the main body for the penetration of the bioactive composition of the drug have a great influence on the penetration of the drug (Gattu and Maibach, 2011).Lipid-water partition coefficients, solubility, melting point, molecular size and shape are widely recognized as important physicochemical factors that influence skin penetration and absorption of drug bioactive composition by their own properties.The strength of the effect of different factors on the penetration of bioactive composition of drugs is closely related to the structural composition of the skin and the prevailing skin condition (Lien and Tong, 1973;Michaels et al., 1975;Roberts et al., 1977).Magnusson et al. found that epidermal permeability coefficient and solute octanol-water partition coefficient were the key factors in the permeation efficiency of pharmaceutical bioactive composition (Magnusson et al., 2004).Molecular weight is an important factor in determining the maximum permeation flux of a pharmaceutical bioactive compound.The permeation of pharmaceutical bioactive compounds is also related to the specific surface area of the particles, the diffusion coefficient of the solute, the thickness of the boundary layer and the solubility of the solute (Sandri et al., 2014).The rate of permeation of a solute from an aqueous solution depends on the efficiency of partitioning and diffusion.The efficiency of solute partitioning in solution is related to the octanol-water partition coefficient.The efficiency of solute partitioning in solution is related to solute size and hydrogen bonding (Zhang et al., 2009).Passive diffusion of drugs through the skin is influenced by the physicochemical properties of the drug bioactive composition and by individualized differences in the structure and physiological state of the skin.However, not all drug bioactive composition penetrates at a higher rate in damaged skin than in normal skin.For example, nicotine transmits at a higher rate through normal healthy skin than through skin previously damaged by corrosive or destructive chemicals or physical agents (e.g., heat and cold) (Macht, 1938).Hydration not only plays an important role in skin barrier function, but also plays a major role in promoting the absorption of drug bioactive composition.Hydration of the stratum corneum can lead to profound changes in skin barrier properties.In its normal state, the stratum corneum contains 15%-20% water, and stratum corneum water can increase to about 400% after over-soaking (Dawber, 1980).Upon absorption by keratinocytes, water alters the position and stability of the disulfide bonds in keratin peptides, causing changes in the spatial orientation of the protein (Walters, 2002).The change in the spatial orientation of the proteins gives more space to the water molecules, allowing the water content of the keratinocytes to increase further.When the keratinocytes themselves swell, the denseness of the structure decreases, the cellular gap between the keratinocytes widens, and the permeability of the skin increases.The hydration of the skin can change the physicochemical properties of the bioactive composition of the drug and increase the diffusion coefficient of the bioactive composition of the drug.As the water content of the keratinocytes increases, the bioactive composition of the drug are more likely to combine with water to form hydrated molecules (Scheuplein et al., 1969;Wiedmann, 1988).In addition to this, pH and temperature also affect the transdermal absorption of drugs.pH is not absolute in its effect on the transdermal absorption of the bioactive composition of a drug.For example, the transdermal absorption dose of indomethacin increases as the pH of the skin surface decreases, a pattern that is not necessarily true for other pharmaceutical bioactive composition (Chiang et al., 1991).Alteration of pH affects the ionization of drug bioactive composition may be the main reason why pH affects the transdermal absorption of drug bioactive composition.Unlike pH, an increase in temperature generally increases the transdermal absorption of drug bioactive composition.Temperature increases skin blood flow at the site of heat application mainly by promoting skin vasodilation, which significantly increases the rate of transdermal absorption of drugs and the dose of transdermal absorption (Barkve et al., 1986;Hao et al., 2016).

Individualized drug use that affects the effectiveness of individualized dosing
The effect of the same drug on different individuals can vary greatly.The main reasons for this difference are family heredity, disease, age, weight and the concurrent use of other drugs.Personalized medicine refers to the formulation of a more reasonable treatment plan with full consideration of each patient's individual situation.Thus, improving the efficacy of drugs, reducing the side effects of drugs in a more economical way achieve better therapeutic effect.

Pharmacogenomics affecting the effectiveness of individualized dosing
As everyone knows genetic sequence varies from person to person by only one in a thousand.Deletion, insertion, duplication and inversion are the four genetic structural variants that are always present.Metabolic enzyme, transporter, receptor and other genes encoding metabolic enzyme regulate the absorption, distribution, metabolism and excretion of substances in the human body.This makes the same concentration of the drug have different therapeutic effects and adverse effects on people with different genotypes.Large studies have shown that adverse drug reactions occurring in hospitals are one of the leading causes of death among American hospital patients (Roden et al., 2019).97%-98% have at least one functional drug-related gene variant (Schärfe et al., 2017).These studies have shown that exploring human drug-related genes is particularly important for individualising medication and improving drug efficacy, hence the emergence of pharmacogenomics.Metoprolol is an important drug in the treatment of various cardiovascular diseases, thyroid crisis and localised choroidal haemangiomas (Zamir et al., 2022).The metabolism of the polymorphic enzyme CYP2D6 is the main reason that affects the metabolic rate of Metoprolol in vivo.In one study, the genotypes of patients were 30% extensive metabolizers, 55% intermediate metabolizers, and 13% weak metabolizers (Anstensrud et al., 2020).If the same drug dose is used in people with the CYP2D6 weak metabolism genotype, the risk of adverse reactions during Metoprolol treatment is 5 times higher than in people with the non-weak metabolism genotype (Bijl et al., 2009).Adjusting Metoprolol dosage according to genotype significantly reduces the probability and severity of adverse reactions in patients.More and more genotypic and phenotypic information related to the pharmacogenome is being discovered and many very useful databases have been established.As of April 2021, PharmGKB contains 715 drugs 1761 genes, 227 diseases, 165 clinical guidelines, and 784 drug labels (Gong et al., 2021).In PharmGKB, we have access to genotypic and phenotypic information related to the pharmacogenome.It includes drug dosing guidelines, drug labelling annotations, clinical and variant annotations, summary of drug-centred pathways, pharmacodynamic genes and the relationship between genes, drugs and disease.Approximately 4/ 5 patients may carry a variant that is a target for commonly prescribed drugs and may also have a functional impact, a variant that may alter drug efficacy (Schärfe et al., 2017).The correct use of gene sequencing tools and pharmacogenomicsrelated databases can effectively guide patients in the rational use of medication, improve drug effectiveness and reduce adverse drug reactions.

Microbiomes influencing the effectiveness of individualized dosing
The human organism contains hundreds of microorganisms with different biochemical functions that are relevant to human life.In recent decades, researchers have discovered that microorganisms also play a role in drug metabolism and efficacy.Zimmermann et al. analyzed 76 bacterial species, metabolizing 271 oral drugs in vitro and found that at least one strain was able to metabolize 2/3 of the drug (Zimmermann et al., 2019).Chemical modification of microorganisms is an important cause of altered drug efficacy.5-aminosalicylic acid has a significant inhibitory effect on intestinal wall inflammation (Tavares Junior et al., 2022).With increased use, resistance develops in most patients.Anaerobic faecal culture experiments have shown that up to onethird of 5-aminosalicylic acid is metabolised by microorganisms to a form that lacks anti-inflammatory activity, N-acetyl-5-aminosalicylic acid (Dull et al., 1987).Mehta et al. identified 12 previously uncharacterized enzyme genes associated with 5-aminosalicylic acid inactivation and found that an increase in the number of these enzyme genes correlated with steroid use (Mehta et al., 2023).Metabolites of microorganisms can also affect the efficacy of drugs.Koh et al. found higher levels of imidazolepropionic acid, a metabolite of the gut flora, in patients who were not well treated with metformin (Koh et al., 2020).Further studies showed that imidazole propionate inhibited metformininduced adenosine 5′-monophosphate-activated protein kinase activation via p38g and Akt, whereas pirfenidone blocked p38γ activation by imidazole propionate and restored the hypoglycaemic effect of metformin inhibited by imidazole propionate.Metabolism of drugs by microorganisms is the source of some adverse drug reactions.Clonazepam is an antiepilepsy and anxiolytic drug, and the breakdown product of this drug, vinylpyrimidine bromide, is severely toxic.Zimmermann et al. found that the serum level of bromoacetyluracil was five times higher in normal mice than in germ-free mice after the use of clonazepam (Zimmermann et al., 2019).The microbiome is relatively new and many of the current studies do not directly benefit patients, but there is no doubt that microbial metabolism has a huge impact on drug metabolism and efficacy.Moreover, the current microbiome research mainly focuses on the intestinal flora, and the research on skin microorganisms is relatively backward, which is not conducive to the research on the individualization of topical medications.Analyzing the reasons why drugs are metabolized by microorganisms can link individual differences in the microbiome to individual differences in drug metabolism, which can be targeted to accurately guide patients in the rational use of medication by restoring the efficacy of the drug or reducing the adverse effects of the drug.

Artificial intelligence modelling of the effectiveness of individualized dosing
Over the past decade, artificial intelligence (AI) has undergone a revolution that is bound to transform economics, society and science, solving many seemingly intractable problems (Richards et al., 2022).In the field of pharmaceuticals, AI has achieved excellent results in data processing, drug discovery (Schneider et al., 2020), image processing (Bera et al., 2021), and chemical structure analysis (Bojar and Lisacek, 2022).However, due to reasons such as medical datasets being difficult to access and the medical field being too large and complex.AI has not really made a real difference in the medical field.As it stands, assisting in disease identification and classification is one of the most promising aspects of AI.Accurate disease delineation and documentation can assist us in identifying and addressing more subtypes of disease further enabling individualized drug delivery.In this context, Acosta proposed a multimodal medical AI model that processes multiple types of information (Acosta et al., 2022).In this model, the AI model is able to make good use of data from both clinical and nonclinical databases, thus truly enabling AI to diagnose and treat diseases.Moor proposed another new paradigm of medical AI (Moor et al., 2023), known as the model of holistic medical AI.This model labelled data, flexibly interpreting data from different combinations of medical patterns and producing expressive outputs through self-supervision of large, diverse datasets.The models of omnipotent medical AI have the ability to customize queries to interact with the model compared to multimodal medical AI models, flexible combinations of different data modalities can be received and results output, allowing inference using undirected tasks.Multimodal medical AI models and all-round medical AI models require a diverse and specialized large database, which is very difficult and requires a very large financial investment.The processing of high-throughput data and the high accuracy requirements of models are also important issues that cannot be ignored in both types of modelling.AI is generally superior to individual physicians in data processing, and it can perform more complex information processing, find new subtypes of disease, and discover links between an individual's characteristics and medication use, leading to better and more precise selection of medication types and dosages for an individual, and thus improving medication efficacy.

Conclusion and outlook
More than half of the world's population uses at least one drug per day, and as the global burden of disease continues to grow, the demand for drugs will continue to increase (Baryakova et al., 2023).Patient compliance is an important factor in disease treatment.Statistically, poor adherence leads to 10% of hospitalizations, resulting in $100 -$300 billion in avoidable healthcare costs and causing approximately 125,000 U.S. patient deaths annually (Baryakova et al., 2023).Oral medication is the most common and highest patient compliance route of medication use.However, most oral medications are not specific and may cause side effects.Metabolism in the gastrointestinal tract and liver can further reduce the dose of bioactive ingredients reaching the target site.Topical administration is a promising and effective method of drug delivery.Topical medication is a highly compliant mode of administration, is not metabolised in the gastrointestinal tract and has a high specificity for skin tissues.
Dermatological diseases are the greatest advantage of topical medication.Topical drugs can quickly reach the target site of skin diseases, shorten the time for the drug to produce therapeutic effects, and avoid the adverse effects of drug hoarding in other tissues.The skin is a complex and sophisticated tissue composed of microorganisms that inhabit the surface layer, cells that make up the structure of the skin, immune cells and their metabolites that are involved in innate immunity, adaptive immunity, and that help to protect the organism against external aggressions, guaranteeing the organism's ability to survive in a harsh and dry external environment.The effectiveness of topical treatments is influenced by a number of factors.The transport of the bioactive composition of a topical drug from the skin to the target site is a key step in the efficacy of topical drugs.Regardless of the target site of the disease, the bioactive composition of topical drugs needs to cross the stratum corneum barrier.Dermatological diseases in which the bioactive composition crosses the stratum corneum barrier and reaches the target site directly to take effect.In subcutaneous tissue diseases, the bioactive composition has to be further diffused and cleared by metabolism and dermal circulation to reach deeper tissues.In diseases of other tissues and organs, bioactive composition also needs to be transported through the bloodstream to reach the target site.Enabling drug penetration through the skin is a major concern for topical drug delivery.The state of the skin barrier, the physicochemical properties of the bioactive composition, the excipients and additives of the agent, the drug delivery system and external means of altering the efficiency of transdermal absorption, such as heat and iontophoresis, all affect the efficiency and dose of the bioactive composition in reaching the target site, and thus the effectiveness of the bioactive composition.Undeniably, the question of how to enhance the transdermal absorption of drugs into the skin is a very important one.The advent of drugs of enormous size, such as proteins, nucleic acids and bacteria, has led to a demand for methods to increase the transdermal absorption of drugs.However, enhancing transdermal absorption of drugs is not the first option to improve the effectiveness of all drugs.Drugs with small molecule compounds as the main bioactive composition are still the most commonly used topical drugs in the clinic.Small molecule actives usually have a very good ability to penetrate the skin.Excessive promotion of transdermal absorption of drugs containing small molecules of biologically active ingredients results in most of the biologically active ingredient entering the bloodstream, while less of the drug is available at the target site of the skin, thus reducing the efficacy of the treatment.If the frequency of use of small molecules is increased, there is a high likelihood of causing adverse reactions in other tissues.Thus, it appears that small molecule topical drugs have a greater need to limit the rate of transdermal absorption.Mineral-based materials, such as apatite, diamond and montmorillonite clay, are currently important in limiting the transdermal penetration of bioactive composition of drugs and maintaining local action (Choimet et al., 2020;Shapira et al., 2022;Wang and Phillips, 2022).However, there are fewer studies of mineral-based materials in topical drug delivery systems, and the mechanism of action is unclear.Research on mineral-based materials as topical drug carriers is a blue ocean and more researchers need to participate in it.
Topical pharmaceutical preparations are emerging as an attractive alternative and a rapidly growing market.A variety of factors can influence the final efficacy.No one topical drug or topical drug delivery system is right for everyone.Individualized medication is an important way to improve the effectiveness of drug use.Individualized precision medication administration also achieves optimal outcomes for patients in a more cost-effective manner and reduces unnecessary capital expenditure.However, the complexity of influencing factors and mechanisms of action yet to be fully explored limit the practical application of precise individual administration of topical drugs.Continuing developments in pharmacogenomics, microbiomics and artificial intelligence modelling are continuing to fill the gaps in theoretical research.However, there is still a long way to go for the application of precise individual medication, and it still requires the continuous joint efforts of all parties.Frontiers in Pharmacology frontiersin.org29 Zhao et al. 10.3389/fphar.2023.1333986

FIGURE 3
FIGURE 3Drug carriers and drug stimulus response elements.(A) is the 12 drug carriers described in the text, which are cell-penetrating peptides, hydrogels, microsponges, polymer films, ionic liquids, deep eutectic solvents, liquid crystals, metal-organic frameworks, bacteria and bacterial derivatives, cells and cell derivatives, silicon dioxide, and calcium carbonate.(B) is the stimulus response element for five drugs described in the text, namely, ligand-mediated targeting of drug-smart response elements, pH-responsive smart response element, redox-responsive smart response element, enzymeresponsive smart response element, and magnetically-responsive drug smart response element.

TABLE 2
The role of different cells in skin diseases.

TABLE 2 (
Continued) The role of different cells in skin diseases.

TABLE 2 (
Continued) The role of different cells in skin diseases.

TABLE 2 (
Continued) The role of different cells in skin diseases.
2. Cytolytic T cells help kill infected macrophages to prevent the spread of the virus 3. CD8 T cells have been shown to eradicate virus-infected monocytes (Continued on following page)

TABLE 2 (
Continued) The role of different cells in skin diseases.

TABLE 3
Advantages, disadvantages and applications of drug carriers.

TABLE 3 (
Continued) Advantages, disadvantages and applications of drug carriers.

TABLE 4
Classification, advantages, disadvantages and applications of drug-smart response elements.