With the increasing incidence, breast cancer has become the most common malignant tumor in females. For women, breast cancer will account for one-third of new malignancies in 2022 and is one of the leading causes of death worldwide (Siegel et al., 2022). The prognosis of breast cancer has been greatly improved with more and more treatment options available, but metastasis is still the cause of poor prognosis and death. According to related reports, about 20%–30% of breast cancer patients may metastasize after the corresponding diagnosis and treatment (Cancer Genome Atlas, 2012). Breast cancer metastases usually occur in the lungs, liver, bone, and brain. The lung is the second most metastatic site of breast cancer, and more than 60% of breast cancer patients develop lung metastases in the advanced stage. Once the tumor has metastasized to distant organs, MBC is largely untreatable due to limited treatment options, and survival after 5 years is only about 20%, however, the overall 5-year survival rate of patients with BCLM is even only 16.8%. The data demonstrates that 60%–70% of patients who die from BCLM (Schlappack et al., 1988; Smid et al., 2008; Nguyen et al., 2009; Eckhardt et al., 2012; Lee et al., 2019; Kim et al., 2021). Despite ongoing efforts by researchers to treat breast cancer, overcoming advanced tumor metastasis is still a great challenge in cancer therapy, which often leads to treatment failure. Therefore, it is a difficult but clinically significant direction in the field of tumor therapy to explore the related treatment for patients of incurable BCLM.

Tumor metastasis is a process involving multiple organs and various cell biology, including the transfer of tumor cells from one organ to another and adaptation to a new TME. Each step of tumor metastasis needs multi-genes and multi-factors to participate in a comprehensive role. At the same time, tumor metastasis is closely related to tumor proliferation, apoptosis, invasion, migration, angiogenesis, and other related genes as well as related signaling pathways (Carmeliet and Jain, 2011). The metastasis of breast cancer to the lung is a multi-layered and complex process, which is influenced by many factors. Relevant data suggest that the incidence of lung metastases in breast cancer varies by molecular subtype, among which triple-negative breast cancer (TNBC) is highly aggressive, approximately 46% of patients with TNBC develop distant metastases, and lung metastases occur in 21%–32%, whereas the median overall survival after metastasis in BCLM is only 13.3 months (Bianchini et al., 2016; Schmid et al., 2018; Medeiros and Allan, 2019; Yin et al., 2020). To clarify the mechanism of lung metastasis of breast cancer and to provide effective targets for precise therapy are the current research ideas of breast cancer metastasis.

At present, in the clinical treatment of breast cancer, the commonly used treatment means are surgery, endocrine therapy, chemotherapy and radiotherapy, and targeted therapy, immunotherapy, and other treatment methods are also being studied (Caswell-Jin et al., 2018; Dahan et al., 2023; Verma et al., 2024). Traditional treatment has a good effect on early breast cancer, but it has little effect on BCLM (Gennari et al., 2021).In addition to poor prognosis, these patients often have a variety of clinical symptoms, including cough, hemoptysis, pleural effusion, and pulmonary dysfunction, which profoundly affect patients’ quality of life and survival (Jin et al., 2018). The application of nanotechnology in the treatment of cancer has provided a new way of thinking about the treatment of cancer, which has gradually become the research hotspot of cancer treatment and made a lot of progress. Treatment of MBC using nanoparticle drug delivery systems has the potential to improve drug delivery, controlled release, and biocompatibility, thus improving drug efficacy and reducing side effects. It is possible to target multiple metastatic sites at the same time and to achieve better therapeutic effects and lower injury effects by combining multiple therapeutic methods (Silberholz et al., 2019; Sudheesh et al., 2022; Rahman et al., 2023). In this review, we attempt to outline the latest advances in the application of nanoscale diagnostic and therapeutic systems for BCLM, with particular emphasis on the mechanisms and research exploration. In addition to presenting experimental validation of BCLM, we discuss potential therapeutic approaches based on nanotechnology that may improve the prognosis of patients with BCLM.

Tumor metastasis generally consists of the following steps (Thiery, 2002): metastatic tumor cells shed from the primary tumor and infiltrate into the surrounding extracellular matrix (ECM), enter the blood or lymphatic vessels, invade and attack distal tissues or organs, settlement of new metastasis, and eventually form distal metastasis. In the process of lung metastasis of breast cancer, we can also regard metastatic breast tumor cells as “seeds,” and the microenvironment provides “soil” during the process of metastasis. “Seeds” are often involved in molecular and functional alterations, while “seeds”are also capable of substance secretion to enhance invasiveness and alter the tumor microenvironment to promote the formation of BCLM. For example, a study has explored that tumor-secreted glucocalcin 1(STC1) can upregulate the expression of S100 calcium-binding protein a 4(S100A4) by promoting the phosphorylation of EGFR and ERK signaling pathways in breast cancer cells to enhance the invasiveness of tumor cells and promote angiogenesis and activation of lung fibroblasts in the metastatic microenvironment, and ultimately promote lung metastasis of breast cancer (Liu et al., 2023). Cancer cell-derived secretory factors can secrete components such as hyaluronan, collagens, laminin and fibronectin via the ER-Golgi pathway and the Golgi-independent pathway, which induce ECM remodeling in the tumor microenvironment, promote cancer cell proliferation, and penetrate tissues and blood vessels, then it spreads to the lungs. Multiple molecules and cellular components secreted by both primary breast tumors and stromal cells, such as PD-L1, P2Y2R, PGE2, transforming growth factor-β (TGF-β), matrix metalloproteinases (MMPs), etc., mediate the complex network of tumor microenvironment, lung stroma, immune cells and bone marrow-derived cells (BMDCs) and provide a fertile niche susceptible for the promotion of breast cancer metastasis to the lung (Paltridge et al., 2013; Medeiros and Allan, 2019; Urooj et al., 2020). For example, Wang et al. (2023) found that Cav-I in BC-derived exosomes regulates the induction of ECM deposition by lung fibroblasts by upregulating PMN(pre-metastatic niche)-associated genes in lung epithelial cells; Inhibition of the alveolar macrophage PTEN/CCL2/VEGF-A signaling pathway to influence M2-type polarization and angiogenesis promotes the formation of a PMN and ultimately leads to breast cancer lung metastasis. In-depth study of the mechanisms of lung metastasis in breast cancer is essential to identify new biomarkers and explore potential therapeutic targets to provide new ideas for possible therapeutic modalities of BCLM. From the point of view of treatment, eradication of the primary tumor, blocking the spread and targeting the metastasis are the three main methods to reduce the tumor metastasis.

For early and middle stage solid tumors, surgical resection can greatly prolong the life span of patients and improve the survival rate of patients, but some studies have shown that surgery and surgical trauma can also promote the formation of new metastases and accelerate the development of micro-metastases (Tohme et al., 2017). Some researchers have reported that circulating tumor cells (CTCs) are associated with tumor metastasis and recurrence after surgery. Surgery inevitably damages the vasculature, disrupts the balance between the immune system and CTCs, and triggers a cascade of local and systemic inflammation. The primary tumor suppresses small metastatic lesions, leaving them in a “dormant state” that maintains a balance between proliferation and apoptosis, but this “homeostasis” is disrupted after surgery, at the same time, the decrease of angiogenesis inhibitor level in the traumatic blood vessels after operation leads to the rapid growth of metastatic lesions (Michelson and Leith, 1994; Valastyan and Weinberg, 2011; Chiarella et al., 2012; Horowitz et al., 2015; Xu et al., 2015). Although some retrospective studies have found that surgery may be a factor in prolonging the survival of MBC, case selection bias may be one of the major reasons for concluding patient benefit (Blanchard et al., 2008; Neuman et al., 2010; Poggio et al., 2018). More and more works of literature show the effect of surgical treatment on metastatic breast cancer, but the survival benefit of surgery has not been clearly established and the choice of surgery in MBC remains controversial (Thomas et al., 2016; Khan et al., 2022; Ren et al., 2024). Some relevant clinical studies (Badwe et al., 2015; Fitzal et al., 2019; Soran et al., 2021; Khan et al., 2022) on the impact of surgery on survival in patients with MBC are listed in Table 1. As far as the current criteria are concerned, it remains to be further discussed whether surgery should be performed for advanced MBC. For advanced metastatic breast cancer, the benefits of local radiotherapy are not well understood, while the lungs are poorly tolerant to radiation and radiotherapy is often palliative (Feys et al., 2015; Zhang et al., 2023). Recent studies have explored new treatment methods such as radiotherapy with hyperthermia, but only play a role in local tumor remission and symptom control.

Few patients with metastatic tumors can be cured by surgical intervention (Steeg, 2006), while systemic therapy has still been a routine treatment for MBC. The conventional methods of systemic therapy for MBC include chemotherapy, endocrine therapy, and molecular targeted therapy. Recent advances in systemic therapy have increased the survival rate of patients with MBC (Caswell-Jin et al., 2018), and traditional chemotherapy is one of the main methods of anti-tumor therapy at present. However, these anticancer drugs have blind-killing effects, can cause severe side effects and varying degrees of drug resistance, and are less effective against breast cancer metastasis and invasion. Some studies have shown that the median progression-free survival time of patients with locally advanced or advanced TNBC treated with first-line chemotherapy is only 5.6 months, and the rate of grade 3 or above related adverse events associated with chemotherapy is high (Cortes et al., 2020). Chemotherapy resistance is often the main cause of chemotherapy failure, especially in MBC and TNBC, and it even accounts for approximately 90% of treatment failures (Nedeljkovic and Damjanovic, 2019). More and more studies have revealed that the development of resistance to MBC chemotherapy is complex and is based on several factors, including the interaction of TME, drug efflux, cancer stem cells, and bulk tumor cells, while changes in multiple signaling pathways control these interactions (Mao et al., 2013; Boelens et al., 2014; Wang et al., 2018; Luo et al., 2020; Gao et al., 2021; Subhan, 2022). At present, in-depth study of chemotherapy drugs has also found their adverse mechanism of action. For example, although paclitaxel is clearly beneficial in reducing tumor size, it alters the lung microenvironment and promotes cancer cells colonizing the lungs (Chang et al., 2017; Keklikoglou et al., 2019). The era of molecular targeted rescue therapy for MBC has come. More and more clinical studies (Hortobagyi et al., 2018; Rugo et al., 2018; Emens et al., 2021; Cortes et al., 2022; Dent et al., 2023; Slamon et al., 2024)confirm the status of targeted drugs and the benefits of the combination of targeted drugs (Table 1). HER2-targeted therapy including mAb, ADC, and small molecule TKIs has important significance in HER2-positive metastatic breast cancer (Swain et al., 2020). PIK3CA mutations are common in metastatic ER-positive breast cancer and can be treated with PI3K inhibitors such as alpelisib (Mayer et al., 2017). PARP inhibitors (PARPI) have antitumor activity in advanced breast cancer and BRCA-mutant patients (Desnoyers et al., 2022). PD-1/PD-L1 inhibitors alone or in combination have been shown to be effective in the treatment of metastatic TNBC (Ren et al., 2022). The continuous updating of therapeutic drugs may change the treatment pattern and survival rate of MBC in the near future. In fact, most drug delivery systems can not precisely target the metastatic site, resulting in poor anti-metastatic effect, so it is important to find new effective metastasis targeting strategies to improve the therapeutic effect of cancer metastasis.

The existing methods of anti-tumor therapy have definite limitations and limited therapeutic effects. Therefore, it is necessary to find a new and effective way of drug delivery to improve the therapeutic effect of tumor metastasis. The nano-drug delivery system is a promising way to break through the dilemma (Schroeder et al., 2011). Compared with traditional drug dosage forms and therapeutic methods, drug delivery systems developed by nanotechnology and new therapeutic methods have unique advantages: increase the solubility of insoluble drugs and decrease their clearance rate; modification on the carrier platform can improve the drug circulation time in tumor and TME, and control the drug release process; the carrier system was modified to respond to the TME and achieve active drug targeting; combined therapy with multi-drug delivery can reduce the single drug resistance of tumor cells and improve the therapeutic efficiency; the drug delivery system was constructed to include imaging drugs for imaging and dynamic observation of tumor (Arvizo et al., 2011; Gurunathan et al., 2018; Palazzolo et al., 2018; Aghebati-Maleki et al., 2020).

In the current studies, the delivery of drugs to tumor cells by nano-carriers often involves three main processes: avoiding the elimination of drugs in the blood circulation when they are outside the cell, increasing the uptake of drugs by cells when they are inside the cell membrane, and accelerating response to cellular environment and releases drugs (The transfer process and influencing factors are shown in Figure 1). Particle size, surface charge, coating ligand, mechanical properties, and chemical properties, as well as route of administration, exhibit different biodistribution, compatibility, degradation, and cycling characteristics, thus have different effects on the anti-tumor process (Hardman, 2006; Schroeder et al., 2011). In the past decades, various types of nanomaterials have been reported for use in anti-tumor processes, and nanomedicine platforms have numerous different compositions and preparation methods. At present, the most widely used nano-drug delivery systems include liposomes, polymers, metals, carbon, biologicals, and so on. (Harisinghani et al., 2003; Voura et al., 2004; Larson et al., 2007; Heller et al., 2008; Lal et al., 2008; Horcajada et al., 2010; Ling et al., 2011; Wang et al., 2011; Qi et al., 2014; Maiolino et al., 2015; Xiao et al., 2015; Zanganeh et al., 2016; Shao et al., 2017; Cai et al., 2018; Patra et al., 2018; Akinc et al., 2019; Bayon-Cordero et al., 2019; Wu et al., 2019; Arshad et al., 2022; Subhan, 2022). (The advantages and uses of nanomaterials for medical diagnosis and treatment are shown in Table 2). Nanomaterials-based drug delivery systems (DDSs) are increasingly considered as a therapeutic option for MBC due to their ability to overcome the limitations of current therapies and provide good safety, controllability, and targeting. Nanoparticles (NPs) carriers currently show good results in cancer patients and various clinical trials.

More and more novel nanoparticle-based targeted DDSs to improve the treatment of BCLM are being studied (Table 3) (Liu et al., 2018; Li et al., 2019a; Cheng et al., 2019; Xiong et al., 2019; Yu et al., 2019; Fan et al., 2020; Gong et al., 2020; Liu et al., 2020; Mu et al., 2020; Shi et al., 2021; Shi et al., 2021; Li et al., 2021; Zhang et al., 2021; Shi et al., 2023; Sabatelle et al., 2024). The process of DDSs to target the metastatic site can be divided into two steps, including one targeting the specific organ where the metastasis is located and the second targeting cancer cells or subcellular organs (Schroeder et al., 2011). At present, there are two strategies for targeted tumor delivery, one is passive targeting, and the other is active targeting. Passive targeting is the enhancement of the permeability and retention (EPR) effect of tumor vessels that leads to preferential aggregation of nanoparticles at tumor sites and increases tumor cell uptake. Active targeting refers to the ligand that binds to the receptor expressed on the nanomaterials, such as the design of albumin nanoparticles, so that the nanomaterials can bind to the receptor of cancer cells, and thus play a targeting role; on the other hand, it can respond to TME or stimulation and achieve the effect of controlled targeted release. Different approaches can maximize the drug’s ability to target and hit tumor cells accurately and reduce the drug’s interference on normal cells, to improve the effect of drugs and reduce the toxic side effects of the meaning of the body.

In recent years, the mode of early diagnosis for advanced breast cancer has been opened up, the drug treatment scheme has been updated, and the surgical scheme has been explored, but the treatment dilemma of BCLM has not been solved. New therapeutic methods, such as immunotherapy and gene therapy, have entered the stage of rapid development and brought new hope for the treatment of tumors. Among them, is the use of nanotechnology for a variety of new ways to provide assistance and play an irreplaceable role. (Nanotechnology applications in the diagnosis and treatment of BCLM in Figure 2).

Lung metastasis is the main cause of death in cancer patients, but there is still a lack of effective treatment for lung metastasis. Traditional treatment methods often lead to the failure of treatment and patients’ intolerance because of drug resistance, systemic tissue toxicity, and lack of effective targeting. New options are therefore urgently needed to overcome the challenges of BCLM-related therapies, particularly in terms of tumor targeting.

In this review, we focus on the application of drug-loaded therapeutic nanoparticles in the treatment of BCLM, specifically targeting the TME as a complex but promising research area. It is not difficult to find that nanoplatform-based therapies for BCLM may have higher efficacy and lower toxicity. At the same time, nanotechnology has shown unique advantages in the immunotherapy and gene therapy of BCLM. More and more researchers will focus on the search for BCLM targets with higher specificity, the use of multi-target synergy to improve the targeting ability, the functionality, and applicability of nanomaterials. Although many preclinical studies have provided new therapeutic ideas and obtained promising results, the clinical transformation of nanoparticles for the treatment of BCLM has been limited so far.

At present, it is difficult for nano-drugs to develop further into clinical practice, which mainly involves the instability and cost of the manufacturing process. At the same time, it is a long and complicated process for researchers to select suitable drug-carrying materials, not only considering the physical chemistry properties of the materials themselves but also there is a need to give serious consideration to biosafety issues that are closely linked to the human body.

In the research of cancer therapy based on nano-systems, the ideal state is that the nano-DDSs are only effective for tumor cells and TME, but this is a difficult process because the mechanisms of tumor cell mutation, tumor metastasis and tumor heterogeneity are not clear yet. Understanding of the pathogenesis of BCLM will also be enhanced in the development of applications targeting nanomedicine, the process that will also accelerate the development of effective BCBM therapy nanomedicine. Currently, the major challenge for nano-drug development is how to achieve complete elimination of the primary tumor and the prevention of tumor metastasis with limited nanomedicine delivery. To date, most cancer nanotechnology therapies have focused on the treatment of primary tumors, but it is important to harness the potential of nanotechnology to fight the spread of cancer at every stage of the metastatic process. We need to devote more effort to further study the valuable practice of nano-platform in BCLM.