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HighlightsThe physiological structure and the drug delivery barriers of lymph nodes were described.The factors affecting lymph nodes accumulation in nano-delivery systems were discussed.The recent progress of nano-delivery carriers applied for lymph nodes immunotherapy was further categorized and reviewed.Immunotherapy has become a promising research “hotspot” in cancer treatment. “Soldier” immune cells are not uniform throughout the body; they accumulate mostly in the immune organs such as the spleen and lymph nodes (LNs), etc. The unique structure of LNs provides the microenvironment suitable for the survival, activation, and proliferation of multiple types of immune cells. LNs play an important role in both the initiation of adaptive immunity and the generation of durable anti-tumor responses. Antigens taken up by antigen-presenting cells in peripheral tissues need to migrate with lymphatic fluid to LNs to activate the lymphocytes therein. Meanwhile, the accumulation and retaining of many immune functional compounds in LNs enhance their efficacy significantly. Therefore, LNs have become a key target for tumor immunotherapy. Unfortunately, the nonspecific distribution of the immune drugs in vivo greatly limits the activation and proliferation of immune cells, which leads to unsatisfactory anti-tumor effects. The efficient nano-delivery system to LNs is an effective strategy to maximize the efficacy of immune drugs. Nano-delivery systems have shown beneficial in improving biodistribution and enhancing accumulation in lymphoid tissues, exhibiting powerful and promising prospects for achieving effective delivery to LNs. Herein, the physiological structure and the delivery barriers of LNs were summarized and the factors affecting LNs accumulation were discussed thoroughly. Moreover, developments in nano-delivery systems were reviewed and the transformation prospects of LNs targeting nanocarriers were summarized and discussed.

Targeting tumour immunosuppressive microenvironment is a crucial strategy in immunotherapy. However, the critical role of the tumour lymph node (LN) immune microenvironment (TLIME) in the tumour immune homoeostasis is often ignored. Here, we present a nanoinducer, NIL-IM-Lip, that remodels the suppressed TLIME via simultaneously mobilizing T and NK cells. The temperature-sensitive NIL-IM-Lip is firstly delivered to tumours, then directed to the LNs following pH-sensitive shedding of NGR motif and MMP2-responsive release of IL-15. IR780 and 1-MT induces immunogenic cell death and suppress regulatory T cells simultaneously during photo-thermal stimulation. We demonstrate that combining NIL-IM-Lip with anti-PD-1 significantly enhances the effectiveness of T and NK cells, leading to greatly suppressed tumour growth in both hot and cold tumour models, with complete response in some instances. Our work thus highlights the critical role of TLIME in immunotherapy and provides proof of principle to combine LN targeting with immune checkpoint blockade in cancer immunotherapy. The tumour lymph node microenvironment is an important contributor to the immune suppressiveness of tumours. Here authors target the tumours and the lymph node simultaneously via a pH and photothermal therapy targeted nanoparticle, and show mobilisation of anti-tumour cytotoxic T cells and NK cells and synergistic therapeutic effect with immune checkpoint blockade.

HighlightsA polarized-macrophages-based drug delivery system (M1/SLNP) was presented for the cell-chemotherapy of cancer.Polarized-macrophages were used both as therapeutic tool to provide immunotherapy and as delivery vessel to target deliver chemotherapeutic drugs to tumor tissues for chemotherapy simultaneously.M1/SLNP was a multifunctional delivery system with simple structure, excellent safety, and without complex synthesis process.Cell therapy is a promising strategy for cancer therapy. However, its therapeutic efficiency remains limited due to the complex and immunosuppressive nature of tumor microenvironments. In this study, the “cell-chemotherapy” strategy was presented to enhance antitumor efficacy. M1-type macrophages, which are therapeutic immune cells with both of immunotherapeutic ability and targeting ability, carried sorafenib (SF)-loaded lipid nanoparticles (M1/SLNPs) were developed. M1-type macrophages were used both as therapeutic tool to provide immunotherapy and as delivery vessel to target deliver SF to tumor tissues for chemotherapy simultaneously. M1-type macrophages were obtained by polarizing macrophages using lipopolysaccharide, and M1/SLNPs were obtained by incubating M1-type macrophages with SLNP. Tumor accumulation of M1/SLNP was increased compared with SLNP (p < 0.01), which proved M1/SLNP could enhance tumor targeting of SF. An increased ratio of M1-type macrophages to M2-type macrophages, and the CD3+CD4+ T cells and CD3+CD8+ T cell quantities in tumor tissues after treatment with M1/SLNP indicated M1/SLNP could relieve the immunosuppressive tumor microenvironments. The tumor volumes in the M1/SLNP group were significantly smaller than those in the SLNP group (p < 0.01), indicating M1/SLNP exhibited enhanced antitumor efficacy. Consequently, M1/SLNP showed great potential as a novel cell-chemotherapeutic strategy combining both cell therapy and targeting chemotherapy.

Cytotherapy is a strategy to deliver modified cells to a diseased tissue, but targeting solid tumours remains challenging. Here we design macrophages, harbouring a surface glypican-3-targeting peptide and carrying a cargo to combat solid tumours. The anchored targeting peptide facilitates tumour cell recognition by the engineered macrophages, thus enhancing specific targeting and phagocytosis of tumour cells expressing glypican-3. These macrophages carry a cargo of the TLR7/TLR8 agonist R848 and INCB024360, a selective indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, wrapped in C16-ceramide-fused outer membrane vesicles (OMV) of Escherichia coli origin (RILO). The OMVs facilitate internalization through caveolin-mediated endocytosis, and to maintain a suitable nanostructure, C16-ceramide induces membrane invagination and exosome generation, leading to the release of cargo-packed RILOs through exosomes. RILO-loaded macrophages exert therapeutic efficacy in mice bearing H22 hepatocellular carcinomas, which express high levels of glypican-3. Overall, we lay down the proof of principle for a cytotherapeutic strategy to target solid tumours and could complement conventional treatment. Macrophages are considered a good candidate for cancer cytotherapy because of their phagocytotic capacity, enabling them to deliver cargo to tissues. Here authors engineer macrophages that are targeted to glypican-3-expressing tumour cells and equipped with drug-loaded exosomes and show therapeutic efficiency in a mouse model of hepatocellular cancer.

Nanodrugs have significantly revolutionized tumor therapy. Nevertheless, conventional nanodrug delivery systems suffer from a critical limitation: only ~0.7% of administered nanoparticles effectively accumulate in solid tumors, severely restricting clinical therapeutic efficacy. In recent years, exosomes-natural extracellular vesicles-have emerged as highly promising candidates for tumor-targeted drug delivery. Endowed with inherent low immunogenicity, excellent biocompatibility, and intrinsic capacity to traverse biological barriers, exosomes offer distinct advantages over conventional nanocarriers. Their characteristic lipid bilayer membrane not only protects encapsulated cargo but also enables surface engineering for functional optimization. Through strategic engineering modifications, exosomes can be endowed with enhanced tumor-targeting specificity, tunable payload release profiles, and multimodal functionalities, thus enabling the development of \"smart\" therapeutic platforms. This review systematically outlines current methodologies for exosome isolation and characterization, with a particular focus on engineering strategies aimed at augmenting tumor targeting. We comprehensively analyze approaches based on physical manipulation, chemical conjugation, and biological engineering. Furthermore, we summarize recent advances in exosome-based targeted cancer therapies and discuss key challenges related to scalability, standardization, regulatory approval, and clinical translation. Finally, we highlight emerging opportunities and future perspectives for next-generation exosome-engineered therapeutic development, aiming to provide a robust technical and conceptual foundation for advancing tumor therapy.

The rising global incidence of central nervous system (CNS) diseases, exacerbated by the formidable blood-brain barrier (BBB) hindering effective drug delivery, necessitates novel therapeutic strategies. Nasal administration has emerged as a promising non-invasive route, bypassing the BBB via direct neural pathways (olfactory/trigeminal), systemic absorption, or lymphatic drainage. However, inherent nasal barriers like the mucus layer and epithelium limit its efficacy. This review distinguishes itself by integrating mechanistic insights into nasal transport pathways with the rational design of advanced nano-delivery systems. We first outline the challenges in CNS drug delivery and detail the nasal anatomy and transport pathways facilitating nose-to-brain delivery. Subsequently, we emphasize the critical properties required of advanced nano-carriers to improve mucosal penetration, prolong retention, and promote drug accumulation at cerebral injury sites. Following a detailed analysis of the advantages and limitations associated with nose-to-brain delivery, we consolidate recent advances in nasal nano-delivery systems for treating CNS disorders, emphasizing their capacity to improve brain-targeting efficiency, enhance therapeutic efficacy, reduce systemic toxicity, and enable previously undruggable CNS targets. Finally, we expand the discussion to encompass current challenges impeding clinical translation, including safety concerns, manufacturing scalability, and regulatory hurdles, while highlighting emerging trends such as artificial intelligence-driven formulation design. This comprehensive analysis aims to deepen the understanding of nasal-to-brain transport mechanisms and inform the future development of effective nasal formulations for improved neurological therapeutics.

Epigenetic modifications regulate gene expression at the transcriptional level, contributing to tumorigenesis and progression. While epigenetic-targeted combination therapies have gained prominence in oncology treatment management, their clinical efficacy remains constrained by differences in pharmacokinetics and biodistribution among combined agents. Nano-drug delivery systems (NDDS) demonstrate unique potential through co-delivery of therapeutic agents and optimization of their pharmacokinetic profiles. Furthermore, the development of multifunctional NDDS opens new possibilities for precision modulation in cancer treatment, offering valuable insights for clinical translation. Here, this review first outlined the intervention mechanisms of epigenetic dysregulation and analyzed the applications of epigenetic combination approaches. Subsequently, we highlight the transformative potential of NDDS in epigenetic combination therapy, with particular emphasis on how multifunctional NDDS design enables precise therapeutic regulation. This comprehensive analysis aims to advance the clinical translation of epigenetic-based combination strategies through innovative drug delivery solutions. In the future, with the continuous development of AI-driven NDDS design, biomimetic carriers, and dynamic epigenetic editing tools, it will be possible to overcome the clinical challenges of NDDS, enabling truly personalized cancer treatment.

Nano-delivery systems have demonstrated great promise in the therapy of cancer. However, the therapeutic efficacy of conventional nanomedicines is hindered by the clearance of the blood circulation system and the physiological barriers surrounding the tumor. Inspired by the unique capabilities of cells within the body, such as immune evasion, prolonged circulation, and tumor-targeting, there has been a growing interest in developing cell membrane biomimetic nanomedicine delivery systems. Cell membrane modification on nanoparticle surfaces can prolong circulation time, activate tumor-targeting, and ultimately improve the efficacy of cancer treatment. It shows excellent development potential. This review will focus on the advancements in various cell membrane nano-drug delivery systems for cancer therapy and the obstacles encountered during clinical implementation. It is hoped that such discussions will inspire the development of cell membrane biomimetic nanomedical systems.

Immune checkpoint inhibitors (ICIs) combined with antiangiogenic therapy have shown encouraging clinical benefits for the treatment of unresectable or metastatic hepatocellular carcinoma (HCC). Nevertheless, therapeutic efficacy and wide clinical applicability remain a challenge due to “cold” tumors’ immunological characteristics. Tumor immunosuppressive microenvironment (TIME) continuously natural force for immune escape by extracellular matrix (ECM) infiltration, tumor angiogenesis, and tumor cell proliferation. Herein, we proposed a novel concept by multi-overcoming immune escape to maximize the ICIs combined with antiangiogenic therapy efficacy against HCC. A self-delivery photothermal-boosted-NanoBike (BPSP) composed of black phosphorus (BP) tandem-augmented anti-PD-L1 mAb plus sorafenib (SF) is meticulously constructed as a triple combination therapy strategy. The simplicity of BPSP's composition, with no additional ingredients added, makes it easy to prepare and presents promising marketing opportunities. (1) NIR-II-activated BPSP performs photothermal therapy (PTT) and remodels ECM by depleting collagen I, promoting deep penetration of therapeutics and immune cells. (2) PTT promotes SF release and SF exerts anti-vascular effects and down-regulates PD-L1 via RAS/RAF/ERK pathway inhibition, enhancing the efficacy of anti-PD-L1 mAb in overcoming immune evasion. (3) Anti-PD-L1 mAb block PD1/PD-L1 recognition and PTT-induced ICD initiates effector T cells and increases response rates of PD-L1 mAb. Highly-encapsulated BPSP converted 'cold' tumors into 'hot' ones, improved CTL/Treg ratio, and cured orthotopic HCC tumors in mice. Thus, multi-overcoming immune escape offers new possibilities for advancing immunotherapies, and photothermal/chemical/immune synergistic therapy shows promise in the clinical development of HCC. Graphical Abstract

Effective presentation of antigens by dendritic cells (DC) is essential for achieving a robust cytotoxic T lymphocytes (CTLs) response, in which cDC1 is the key DC subtype for high‐performance activation of CTLs. However, low cDC1 proportion, complex process, and high cost severely hindered cDC1 generation and application. Herein, the study proposes an in situ cDC1 recruitment and activation strategy with simultaneous inhibiting cancer stemness for inducing robust CTL responses and enhancing the anti‐tumor effect. Fms‐like tyrosine kinase 3 ligand (FLT3L), Poly I:C, and Nap‐CUM (NCUM), playing the role of cDC1 recruitment, cDC1 activation, inducing antigen release and decreasing tumor cell stemness, respectively, are co‐encapsulated in an in situ hydrogel vaccine (FP/NCUM‐Gel). FP/NCUM‐Gel is gelated in situ after intra‐tumoral injection. With the near‐infrared irradiation, tumor cell immunogenic cell death occurred, tumor antigens and immunogenic signals are released in situ. cDC1 is recruited to tumor tissue and activated for antigen cross‐presentation, followed by migrating to lymph nodes and activating CTLs. Furthermore, tumor cell stemness are inhibited by napabucasin, which can help CTLs to achieve comprehensive tumor killing. Collectively, the proposed strategy of cDC1 in situ recruitment and activation combined with stemness inhibition provides great immune response and anti‐tumor potential, providing new ideas for clinical tumor vaccine design. An in situ hydrogel vaccine is fabricated by co‐encapsulating Fms‐like tyrosine kinase 3 ligand (FLT3L), Poly I:C, and Nap‐Ce6/UCM (NCUM). Ce6 triggered Photodynamic therapy (PDT) induces tumor antigens release in situ. cDC1 is recruited to tumor tissue and activated for cross‐presentation, followed by migrating to lymph nodes and activating CTLs. Tumor stemness is inhibited by napabucasin, which helps CTLs to achieve comprehensive tumor killing.