The biosafety of sericin has long been controversial. Studies have confirmed that sericin has good biocompatibility from the three standpoints of inflammation, allergy, and immunogenicity: (i) sericin only causes low response of inflammatory cells in vivo (macrophages and neutrophils) (Jiao et al., 2017; Li et al., 2015) (Figures 1A, B); (ii) neglected allergens (Jiao et al., 2017) and (iii) sericin only causes mild innate and adaptive immune responses (Jiao et al., 2017; Zhang et al., 2006; Zhang Y. et al., 2021; Panilaitis et al., 2003). Furthermore, the addition of sericin to a mixture of chitosan and silver nanoparticles (AgNPs) can reduce their immunogenicity (Nayak et al., 2021). Various forms of materials such as nanoparticles, hydrogels, scaffolds, sponges and films prepared from sericin have also not been found to cause marked immune responses or inflammatory reactions (such as mast cell degranulation) (Hassan et al., 2024; Ampawong and Aramwit, 2016). An important reason for the low immunogenicity of serine is that it is rich in hydrophilic amino acids. Inspired by this, poly-β-homoserineand poly-DL-serine materials can substantially reduce foreign body reactions and are expected to replace polyethylene glycol as an ideal implantable biological material (Zhang et al., 2020; Zhang D. et al., 2021) (Table 1).

Inflammation is the body’s defense response to injury or infection and involves a variety of cellular and molecular mechanisms. In the process of tissue healing, inflammatory cells such as macrophages and neutrophils are first recruited to the injury site and release pro-inflammatory factors such as interleukin-1 beta (IL-1β), IL-6, tumor necrosis factor α (TNF-α), etc. These factors promote vascular dilation and increased permeability, attracting more immune cells to participate in the inflammatory response. It also activates the degradation and remodeling of extracellular matrix. Subsequently, anti-inflammatory factors such as IL-4 and IL-10 begin to play a role, inhibiting the production of pro-inflammatory factors, reducing the activity of inflammatory cells, and promoting tissue repair and regeneration (Eming et al., 2017). The balance of inflammation and inflammatory factors is crucial for tissue healing. Excessive inflammatory response may lead to increased tissue damage, while insufficient anti-inflammatory factors may delay the healing process.

Sericin preparations have found application in skin repair, blood sugar reduction, and treatment of acute myocardial infarction (Wang D. et al., 2022; Aramwit et al., 2013; Tuentam et al., 2022; Song et al., 2016) (Figure 1C). There are three main mechanisms through which sericin inhibits the inflammatory response: (i) inhibits infiltration and proliferation of inflammatory cells (Zhaorigetu et al., 2003; Chlapanidas et al., 2013); (ii) inhibits expression of IL-1β, IL-6, IL-23, etc (Song et al., 2016; Chlapanidas et al., 2013; Deenonpoe et al., 2019; Kumar J. P. et al., 2018; Dong et al., 2020; Farajdokht et al., 2021); and (iii) increases the expression of IL-4 andIL-10, etc (Seyedaghamiri et al., 2021; Aramwit et al., 2018) (Figures 1D, E). Notably, Sun et al. revealed the mechanism of sericin inhibiting lipopolysaccharide (LPS) induced inflammation by multi omics integration: (i) sericin inhibits LPS-activated PRRs, Toll-like receptors and NOD-like receptors pathways; (ii) sericin significantly downregulates the expression of the MyD88 and NOD1; (iii) sericin decreases the expression of IL-1β, IL-6, INOS, etc (Sun et al., 2022). Interestingly, I-sericin is induced by γ-irradiation of sericin, and exhibits potent anti-inflammatory activities as the parent molecule, including reduction of oxidative stress-induced inflammatory cytokines cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), TNF-α, IL-1β and alleviation of LPS-induced inflammation (Choi et al., 2023; Song et al., 2020).

Sericin reportedly modulates epidermal immune responses in patients with psoriasis by reducing cytokine production by Th17 cells, upregulating galectin-3 (Lgals3) and down-regulating sphingosine-1-phospholyase 1 (Sgpl1) (Rujimongkon et al., 2021). As recently shown, low molecular weight (LMW) sericin (<10 kDa) enhances immune regulation in vitro: LMW-sericin (0.1 mg/mL) can upregulate the expression of CXCL9, IL-12A, BMP-7, and IL-10 in macrophages; balance Th1 and Th2 levels; and induce M2 polarization of macrophages. Sericin regulates macrophage proliferation to achieve immune regulation (Cherng et al., 2022) (Figure 1F). In addition, I-sericin has immune-enhancing effects, manifested as a significant increase in lymphocyte proliferation and activation of NK cells (Song et al., 2020). In addition, biosynthetic sericin 1-like protein can induce tolerant dendritic cells (DCs), which have excellent immunomodulatory capabilities. The purity of sericin 1- like protein is positively correlated with the anti-inflammatory effect of sericin; therefore, it is expected to be developed as an immune modulator (Song et al., 2020; Ritprajak et al., 2021).

In summary, the good biocompatibility and low immunogenicity of sericin are now widely recognized, making it a new avenue for drug delivery and tissue engineering (Wang C. et al., 2022; Sapru et al., 2021). Moreover, the anti-inflammatory properties and good immune regulatory functions of sericin will greatly expand its clinical applications.

SF can achieve solution-gel transition by altering the pH, temperature, and solvation state, or by increasing biopolymer dynamics (Matsumoto et al., 2006). Studies on the biocompatibility and low immunogenicity of hydrogels are often based on the histological evaluation of tissue reactions, with the main focus of observing changes in inflammatory markers, such as neutrophils, eosinophils, and macrophages, in the SF hydrogel and the surrounding tissues (Fu et al., 2022; Etienne et al., 2009; Maity et al., 2022) (Figure 2A). However, these methods are not sufficiently precise to determine the biocompatibility and low immunogenicity of SF hydrogels. Therefore, advanced equipment and technical means are required to explore the inflammatory reaction caused by SF hydrogels in detail. Recently, using noninvasive bioluminescence imaging, Gorenkova et al. demonstrated that SF hydrogels elicited an acute but mild local inflammatory response in vivo, which elicited an innate immune response similar to that elicited by polyethylene glycol (PEG) hydrogels (Gorenkova et al., 2021) (Figure 2B). The Forster/fluorescence resonance energy transfer (FRET)-based sensor experiment developed by Kambe et al. first exposed the initial immune response of SF hydrogels. SF hydrogels are surrounded or invaded by matrix metalloproteinases (MMP) within 24 h after implantation and undergo biodegradation within 3 h after implantation, which may favor immune cells (macrophages, foreign body giant cells) to achieve major degradation of the hydrogel over a period of weeks (Kambe and Yamaoka, 2021; Janani et al., 2022) (Figure 2C).

The surface morphology, physical structure, and chemical structure of the scaffold play a decisive role in the reaction with immune cells, and these features also regulate macrophage polarization at the host tissue implant interface (Antmen et al., 2021). The SF scaffold reportedly has good biocompatibility and low immunogenicity through histological and immunofluorescence staining analysis (Fu et al., 2022; Wang et al., 2008; Guan et al., 2013; Yang et al., 2021; Ge et al., 2012; Suzuki et al., 2019; Singh et al., 2018). Recent studies have revealed the effects of SF scaffolds on macrophages. SF scaffold implants can inhibit classical activated macrophages (M1) and stimulate alternatively activated macrophages (M2) to regulate local inflammatory responses (Janani et al., 2022; Yang et al., 2021). Mast cells, an important type of immune cells, can be activated by biomaterials, which can trigger inflammation by releasing histamine, cytokines and other mediators, promote recruitment and activation of macrophages and other immune cells, and affect the immune microenvironment at the transplant site of biomaterials. Garg K et al. found that SF scaffolds were not conducive to mast cell adhesion and proliferation, suggesting that they were largely immune inert (Garg et al., 2011). The origin, protein conformation, amino acid sequence, fiber thickness, and porosity of SF play important roles in determining the macrophage phenotype, monocyte responsiveness, and T-cell activity (Janani et al., 2022; Yang et al., 2021; Bhattacharjee et al., 2013). Therefore, it is necessary to consider factors that affect the immune response when designing SF scaffolds.

Evaluation of the innate and adaptive immunity of SF nanoparticles (SFNPs) in vivo demonstrate low immunogenicity and anti-inflammatory properties (Zhang Y. et al., 2021). SFNPs play an anti-inflammatory role and immunomodulatory properties in intestine of trinitrophenyl sulfonic acid-induced experimental colitis in rats, which is specifically manifested as reducing neutrophil infiltration, decreasing the expression of IL-1β and promoting the expression of IL-10, while functionalization of arginine–glycine–aspartic acid (RGD) peptide can significantly improve its anti-inflammatory properties (Rodriguez-Nogales et al., 2016) (Figure 2D). In addition, a SF nanosilk solution reportedly reduces gene expression of the proinflammatory factor IL-6 accompanied by a tendency to reduce inflammatory cell infiltration early in the healing process (Niemiec et al., 2020) (Figure 2E).

SF films are also biocompatible, have low immunogenicity, and can reduce the infiltration of inflammatory cells. SF films are mainly used in wound healing and tissue repair (Ge et al., 2012; Arthe et al., 2020; Yao et al., 2019) (Figure 2F). In addition, the transparent artificial dura made from SF effectively reduces the expression of IL-1β, IL-6, and TNF-α (Kim et al., 2011).

Notably, peptides produced by SF hydrolysis exhibit anti-inflammatory potential. SF peptide alone inhibits TPA-induced increase in COX-2, IL-6, IL-1β, and TNF-α levels, and significantly enhances the anti-inflammatory activity of Tat-SOD and PEP-1-FK506 binding proteins (Kim et al., 2011; Kim et al., 2012). γ-irradiated SF significantly enhances various aspects of the immune systems by activating NK cells, T-cell proliferation, NO production, and increasing cytokine levels (Byun et al., 2010). The anti-inflammatory potential of the SF hydrolysate and irradiation products suggests that further processing and treatment of SF will be a new strategy to explore its value.

Small interfering RNA (siRNA) is essential for the effective inhibition of tumorigenesis, targeting of tumor metastasis, and activation of tumor-associated immune cells via silencing the specific gene (such as p65 and PD-L1) responsible for different cancer hallmarks (Ngamcherdtrakul and Yantasee, 2019). Using an effective delivery system, siRNAs can be selectively targeted to tumor microenvironment (TME), sent to regulatory T cells (Tregs), macrophages, myeloid-derived suppressor cells, and other cells to “silence” immunosuppressive cells, and enhance therapeutic immunotherapy (Deng K. et al., 2022; Qian H. et al., 2022; Li S. Y. et al., 2016; Hossain et al., 2015). Currently, sericin as a biological material has been designed as a delivery system for targeted delivery of siRNA. For example, a system consisting of superparamagnetic iron oxide nanoparticles (SPIONs) modified with sericin can target triple-negative breast cancer, accelerate tumor necrosis, and inhibit tumor proliferative growth (Shirangi et al., 2022). Furthermore, hyaluronic acid/poly-L-lysine-siRNA/albumin-sericin (2:1) nanoparticles can be used as siRNA delivery system for laryngeal cancer treatment (Yalcin et al., 2019). Therefore, it is expected that, in the future, serine will be increasingly used as a biological material to design a drug delivery system to target siRNA to immunosuppressive cells in the TME, which will be a potential new direction for enhancing immunotherapy.

Photothermal therapy (PTT) and photodynamic therapy (PDT) are two novel cancer treatments. Their anti-tumor efficacy can be improved by inducing non-invasive pyroptosis of cancer cells and stimulating anti-tumor immune responses. For example, recently prepared VB12-Sericin-PBLG-IR780 nanomicelles not only trigger programmed pyroptosis in cancer cells but also activate DC maturation, initiate T-cell recruitment, and play a key role in anti-tumor processes (Guo et al., 2022) (Figure 3A).

In addition, during the treatment for tumors, although the use of chemotherapy drugs inhibits tumor formation and development, it can also have a negative impact on the immune system. Lactoferrin (LF), a common iron-binding glycoprotein, not only has the function of regulating iron metabolism, but also plays a crucial role in antibacterial, antiviral, anti-tumor and immune regulation (Jańczuk et al., 2022). A sericin hydrogel system for the delivery of recombinant human LF (SSH-rhLF) can prolong the bioactivity and bioavailability of rhLF and may have a therapeutic effect on the cyclophosphamide (CTX) induced immunosuppression mice by enhancing the function of liver macrophages, promoting the expression of immunoregulatory factors (IL-2, IL-21, IL-18, and CD-3), and promoting the proliferation of splenic lymphocytes (Xu et al., 2021). This provides a new strategy for enhancing immunity in patients undergoing cancer chemotherapy.

Atopic dermatitis (AD) is a common chronic inflammatory disease, for which immunotherapy is an important treatment (Li and Man, 2022). Sericin prepared in emulsion gel and hydrogel forms is very effective in correcting the abnormal immune response caused by AD by loading levocetirizine (an antihistamine), anti-RelA siRNA, and functional peptides (Pal et al., 2019; Kanazawa et al., 2015) (Figure 3B). Intra-articular injection of sericin hydrogel preparations containing anti-RelA siRNA also has great therapeutic potential for the treatment of rheumatoid arthritis (RA) (Kanazawa et al., 2017). Moreover, sericin-based microspheres loaded with racemic flavanone naringenin (a TNF-α blocker) helped to suppress LPS-induced serum TNF-α levels, which mediate immune disorders in psoriasis, and thus are expected to be a new modality for psoriasis immunotherapy (Chlapanidas et al., 2014).

Macrophages are among the first cells to arrive at and interact with implanted materials and involved in regulating the resolution of inflammation, promoting tissue repair and regeneration. Mature macrophages are polarized into M1 or M2 subtypes. Classically activated M1 induced by IFN-γ, exhibit a proinflammatory phenotype. Activated M2 induced by IL-4 or IL-13 exhibit an anti-inflammatory phenotype (Kumar et al., 2016). During tissue repair, excessive and prolonged activation of proinflammatory M1 macrophages in the early stages of inflammation can lead to increased inflammation, thereby impairing tissue repair and regeneration (Martin and García, 2021; Bessa-Gonçalves et al., 2023). Therefore, accelerating the change in the macrophage from M1 to M2 is an important strategy in both biomaterial development and tissue repair/regeneration.

The polarization response of macrophages to biomaterials is currently being explored in three main approaches: (i) immunofluorescence staining using M1 surface markers (such as chemokine receptors 7, CCR7) and M2 surface markers (such as CD206) and observing results (Wang et al., 2020); (ii) determining cytokine secretion profiles of macrophages, which indirectly reflect macrophage phenotype (Wang et al., 2020; Chachlioutaki et al., 2022); (iii) examining the expression of M1 and M2 genes (Wang et al., 2020; Zhang et al., 2017; Jiang et al., 2021a). Sericin composite biomaterials in the form of scaffolds, films, hydrogels, and other treatments combined with drugs such as ketoprofen (an anti-inflammatory agent), nerve growth factor, and exosomes inhibit inflammatory responses by promoting macrophage M2/M1 conversion, which is exploited for tissue and peripheral nerve repair (Chachlioutaki et al., 2022; Zhang et al., 2017; Jiang et al., 2021a). Recently, the bone immune microenvironment, in which macrophages play a key role in reprogramming of the bone regeneration and immune microenvironment, has attracted increasing attention. Sericin released in an injectable alginate/serin/graphene oxide (Alg/Ser/GO) hydrogel promotes M2 polarization and migration through nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling, inducing osteogenic differentiation and bone regeneration (Jiang et al., 2021a). Se-CuSrHA@ (epigallocatechin -3- gallate) EGCG (Figure 3C), a sericin-based nanoplatform, increases mRNA level of Arg-1 and CD206, increases the secretion of anti-inflammatory cytokines, inhibit M1 while promoting the polarization of M2, balanced immune homeostasis, and accelerating bone regeneration (Ming et al., 2025). In another study, serine incorporated into a gelatin sponge polarizes M1 macrophages and promotes bone morphogenetic protein 2(BMP-2) secretion to enhance osteogenesis (Jo et al., 2021). Therefore, the factors through which sericin materials determine macrophage phenotypes may be complex and require further exploration.

Sericin-composite biomaterials can also inhibit inflammatory cell proliferation and infiltration in the treatment of inflammatory diseases. Sericin-loaded alginate nanoparticles significantly reduce polymorphonuclear cell (PMN) infiltration and inhibit carrageenan-induced paw edema (Khampieng et al., 2015). The sericin/proanthocyanidin (PAC) composite reverses histological damage, including inflammatory cell infiltration and goblet cell loss, slowing disease progression and is a promising alternative therapeutic strategy for dextran sulfate sodium (DSS) -induced ulcerative colitis (UC) (Wang C. et al., 2022). In addition, the reduction of inflammatory cells in the surrounding tissues was observed at the initial stages of implantation of the alginate/sericin/graphene oxide (Alg/Ser/GO) hydrogel, which is conducive to bone regeneration (Jiang et al., 2021a). Sericin can promote chondrocyte differentiation and growth by activating the Smad2/3/TGF-β pathway and regulate local proinflammatory responses (Fongsodsri et al., 2024).

In terms of wound treatment, carboxymethyl cellulose/sericin-based hydrogel dressing can downregulate the IL-1β, IL-6, and TNF-α to improve the pro-inflammatory response at the diabetic wound site (El-Samad et al., 2022; Bai et al., 2023). Hydrogels made of fibroin and sericin are excellent at promoting wound healing and reducing inflammation (Zhang D. et al., 2024; Ashraaf et al., 2023). Using sericin as a biological template, CuS@Ser NPs stimulate angiogenesis and inhibited inflammation, thereby facilitating rapid wound healing (Guo et al., 2023).

Another bacterial cellulose wound dressing made from sericin/polyhexamethylene biguanide has a strong ability to promote tissue secretion of IL-4 and TGF- β, thereby achieving a more efficient regulatory ability to promote wound treatment (Napavichayanun et al., 2018). In terms of psoriasis treatment, the combination of naringin and sericin in equal proportions significantly reduced the production IL-6, TNF-α and IL-23 in patients (Deenonpoe et al., 2019). Sericin-based poly (vinyl) alcohol (SS/PVA) hydrogel alleviates the development of psoriasis symptoms by up-regulating nuclear factor erythroid 2 related factor 2 (Nrf2), IL-10, and down-regulating TNF-α and IL-20 (Tuentam et al., 2022). In terms of colitis treatment, sericin composite biomaterials can alleviate UC by reducing the levels of proinflammatory cytokines TNF-α, IL2, IL-6, IL-17, and IL-12 and upregulating the levels of the anti-inflammatory cytokine IL-10 (Xu et al., 2022; Fongsodsri et al., 2024; Ma et al., 2019). The mixture of sericin and curcumin can inhibit carrageenan-induced foot edema in mice by suppressing the release of IL-1 β, promoting the secretion of IL-4 and IL-10 (Ashraaf et al., 2023).

The sericin composite biomaterials loaded with drugs can be used to treat inflammatory diseases by reducing the release of proinflammatory mediators, upregulating anti-inflammatory cytokines and macrophage polarization (Jiang et al., 2021a; Chu et al., 2023) (Figures 3D, E). Sericin base biomaterial is a new and gradually emerging therapeutic strategy for wound treatment.

SF has biocompatibility, controlled-release characteristics, and excellent mechanical and biological properties, such as immunomodulatory and anti-inflammatory properties, making it an excellent choice for the construction of composite biomaterials for tumor immunotherapy. Surface-engineered SF nanocomposites not only exhibit excellent anti-tumor functions but can also be combined with different types of tumor therapies to enhance tumor immunotherapy. The related mechanisms mainly include: (i) reversal of the immunosuppressive TME, including inducing the transformation of tumor-associated macrophages from M2 to M1 and reducing the number of Tregs (Zhang X. et al., 2022; Yu et al., 2022a; Tan et al., 2020; Yu et al., 2023) (Figures 4A, B); (ii) induction of immunogenic cell death (ICD) to stimulate anti-tumor immunity (Zhang X. et al., 2022; Yu et al., 2022a; Tan et al., 2020; Yu et al., 2023; Tkach et al., 2017); and (iii) promotion of the maturation of DCs, the formation of effector T cells and effector memory T cells to improve immune activation and promote immune memory (Zhang X. et al., 2022; Yu et al., 2022a; Tan et al., 2020; Tkach et al., 2017; Cao et al., 2022) (Figures 4A–C).

Transcutaneous immunization (TCI) enhances tumor immunotherapy by delivering antigens to DCs through skin. Compared to traditional oral or injection vaccinations, it has the advantages of excellent immunogenicity, avoidance of the liver first-pass effect, good compliance, safety, high efficiency, non-invasiveness, and ease of use (Karande and Mitragotri, 2010). However, the presence of a cuticular barrier leads to a low transdermal delivery efficiency of TCI, thereby limiting its large-scale clinical application. SF has good biocompatibility, air permeability, and skin affinity, and can mimic the extracellular matrix, making it a good biological material for constructing transdermal drug delivery systems. Composite biomaterials constructed using SF can Stimulate cellular and humoral immune responses and induce systemic anti-tumor response by improving the transdermal properties of transdermal carriers, targeting, and inducing DCs maturation (Yang et al., 2020; Song et al., 2022). According to recent researches, the combination of SF-constructed percutaneous tumor immune materials and immune checkpoint blockers, such as programmed cell death protein 1 monoclonal antibody (aPD-1) which can enhance T-cell responses and mediate preclinical antitumor activity by blocking the binding of PD-1 on T cell with PD-L1 on cancer cells, may be a new strategy for effectively enhancing tumor immunotherapy. The involved mechanisms include: (i) promotion of the infiltration of CD4 and CD8 T cells into the tumor tissue, and (ii) promotion of the expression of IL-12, IFN-γ, and TNF-α (Song et al., 2022; Hong et al., 2021).

It is also of interest that SF has been used as a vaccine carrier for cancer immunotherapy. For example, Lei et al. recently developed an injectable SF microsphere loaded with an antigen and an immune adjuvant. Its macroporous structure is conducive for the recruitment of immune cells and can promote the activation of DCs to forms a favorable immune microenvironment. In turn, strong humoral and cellular immunity is induced. In addition, an enhanced vaccine modified by adsorbing antigens on SF microspheres effectively inhibits tumor growth by improving the cytotoxic T lymphocyte (CTL) response (Lei et al., 2022), properties that encourage a new approach for the future development of tumor immunotherapy vaccines.

Antigen delivery dynamics can influence the immune response to vaccines. For example, vaccine antigens can induce sustained humoral immunity after they are delivered to the lymph nodes to trigger naïve B cell response, whereas traditionally injected immunization can rapidly eliminate antigens, which is not conducive to the establishment of humoral and cellular immunity. Improving the immunogenicity of vaccine antigens and maintaining their slow release are new strategies for enhancing vaccine efficacy. The ability of the SF matrix to enclose and release intact and bioactive immunologically active materials has attracted much attention in the construction of slow-release novel vaccines (Reeves et al., 2015; Guziewicz et al., 2011; Kumar M. et al., 2018) (Figure 4D). The microneedle patch combined with the SF matrix can achieve the continuous release of vaccine antigens, enhance the immunogenicity of the vaccine, and thereby significantly enhance the degree, duration, and breadth of the humoral and cellular immune responses caused by the vaccine. Therefore, this represents a promising vaccine delivery strategy at present (Boopathy et al., 2019; Stinson et al., 2021; DeMuth et al., 2014) (Figure 4E).

SFNPs can enhance antigen target delivery, immunogenicity, and stability and can release antigens slowly and continuously, making them a promising new vaccine preparation. SFNPs was used as nanoadjuvants to deliver recombinant hepatitis B surface antigen (HBsAg) and FimH-IutA antigen, with the resulting vaccine significantly increasing the content of specific antibody IgG and promoting humoral and cellular immune responses (Rezaei et al., 2021; Hasanzadeh et al., 2020). Similarly, SF, which presents the advantages of sustained release, absorption, and in situ gelation in various tissues, has been used as a mucosal vaccine carrier. This vaccine carrier not only alleviates gastric injury but also leads to significant infiltration and generation of CD4 tissue-resident memory T (TRM) cellsin gastric epithelial tissues, which are the key mediators of anti-infection immunity in various tissues and have recently been shown to boost local stomach immunity (Schenkel et al., 2014; Xu et al., 2019; Hu et al., 2020) (Figure 4F).

CpG oligodeoxynucleotides (CpG ODNs) are short single-stranded synthetic DNA molecules which are designed to mimic bacterial DNA. These molecules are recognized by Toll-like receptor 9 (TLR9), which is expressed in certain immune cells such as myeloid cells, thus possess potent immune-stimulatory properties (Hekmatshoar et al., 2019). SFNPs have been used as effective carriers of CpG ODNs, which can significantly improve the delivery of CpG ODNs, as shown by the significantly enhanced cellular uptake and significantly increased levels of cytokines and nitric oxide produced following CpG ODN stimulation (Zhang et al., 2019).

SF has particularly excellent biocompatibility and can slowly degrade in vivo, has an excellent mechanical strength, and increases cell adhesion. Injectable hydrogels prepared by combining SF with other materials achieve controlled biodegradation and low mass loss and can be loaded with immunosuppressive agents such as methylprednisolone and betamethasone for cartilage regeneration and the treatment of rheumatoid arthritis (Phan et al., 2022; Oliveira et al., 2020).

Human bone marrow mesenchymal stem cells (hBMSC) are widely used in cell therapy because of their powerful proliferative and immune-regulatory abilities. SF films reportedly preserve not only the immunosuppressive effects of hBMSCs on T-cell proliferation and cytokine release, but also IL-6 secretion, and the immunophenotypes of hBMSCs (Luan et al., 2009).

M2 macrophage polarization is an important immune regulatory event that reduces inflammation during wound repair, bone regeneration and repair, and colitis repair. Many composite biomaterials targeting this key event have been developed based on the excellent mechanical properties, biocompatibility, and bioactivity of SF. For example, Silk-6/ε-PL@Exo (constructed from SF/poly-L-lysine hydrogel) controls inflammation, inhibits glycolysis and lactic acid accumulation by targeting M1 macrophages, and promotes the polarization of macrophages from M1 to M2 (Jin et al., 2024). The inflammatory response induced by SF is not fixed: SF/nano-hydroxyapatite scaffolds trigger a proinflammatory response by M1 macrophages on the first day, whereas SF degradation products induce an anti-inflammatory response by M2 macrophages on the day 24 of treatment (Wong et al., 2024). Lv et al. found that SF treated with reagents such as acetic acid and sodium hydroxide increased the expression of proinflammatory cytokines in rats and accelerated their degradation in vivo. Overall, most studies suggest that SF has good biocompatibility and anti-inflammatory properties.

Owing to the dissolution of the scaffold by protease K in the body, the secondary/tertiary structure of SF is altered, leading to significantly different immune responses. Maintaining the stability of SF in the body is of great clinical value, and bioactive gold cluster sutures (clusters assembled on the SF surface) ensure the structural stability of SF for 15 months without degradation in vivo (Tian et al., 2024).

Composite biomaterial systems in the form of hydrogels, scaffolds, and nanoparticles prepared using SF can be loaded with anti-inflammatory drugs, endowing them with anti-inflammatory activity by inhibiting the infiltration and proliferation of inflammatory immune cells. For example, SF hydrogels loaded with EGCG, rhein, and glycyrrhizic acid can effectively reduce the infiltration and proliferation of inflammatory cells (Qian Y. et al., 2022; Yin et al., 2022; Lee et al., 2022; Zhang F. et al., 2022). For the scaffold system, a gelatin sponge scaffold modified with neurotrophin-3 (NT-3)/SF can achieve a controlled-artificial release system with significant inflammatory inhibitory activity in the rat spinal cord injury (SCI) model, as shown by a significant reduction in the number of IBA-1 positive and CD68 positive macrophages/microglia (Li et al., 2018; Li G. et al., 2016). SF NP drug delivery systems loaded with bromelain and ZnO NPs, EGCG and Tubasatin A is effective in reducing the massive infiltration and proliferation of inflammatory cells (Liu et al., 2022; Hasannasab et al., 2021; Xie et al., 2022; Liao et al., 2022) (Figure 5C).

In particular, it is worth noting that SFNPs have anti-inflammatory properties, which can inhibit the infiltration and proliferation of inflammatory immune cells and can cooperate with anti-inflammatory drugs to exert anti-inflammatory effects. Therefore, SFNPs are a suitable choice for the preparation of anti-inflammatory composite biomaterials.