The functional reconstruction of bone defects caused by trauma, infection, surgical resection and degenerative diseases poses substantial clinical challenges. Bone tissue engineering (BTE) holds immense potential for treating bone defects while avoiding complications commonly associated with conventional autografts, allografts and internal fixation. Bioactive hydrogels with exceptional drug delivery capabilities, excellent biocompatibility and tunable physicochemical properties have emerged as promising biomaterial scaffolds for BTE. This review provides a comprehensive overview of recent advancements in bioactive hydrogel-based strategies for BTE applications. An initial introduction to bone physiology is followed by a critical discussion of the design considerations for hydrogel platforms, specifically biomaterial selection, innovative crosslinking mechanisms and bioactive functionalization. Furthermore, hydrogel engineering for the controlled delivery of bioactive cargo is critically examined, with an emphasis on spatiotemporally programmable release behaviors that coordinate osteogenesis, angiogenesis and immunomodulation. Finally, key translational challenges are discussed, and the emerging role of artificial intelligence-assisted design is explored as a transformative approach for facilitating the clinical translation of next-generation bioactive hydrogels for BTE.
Therapeutic monoclonal antibodies have revolutionized the treatment of cancers, infectious diseases and immune disorders; however, their efficacy is compromised by limitations associated with systemic administration, including systemic toxicity, poor patient compliance and inadequate drug concentration at pathological sites. Hydrogels are promising carriers for localized antibody delivery, but conventional formulations fail to simultaneously address the dual challenges of uncontrolled antibody release and insufficient hydrogel retention at the target site. Herein, leveraging a peptide co-assembly strategy, we engineered an injectable dual-affinity self-assembling peptide hydrogel for localized antibody delivery. This hydrogel integrates three components: peptide FEK as the hydrogel matrix, MEP-FEK incorporating 4-mercaptoethylpyridine (MEP) for non-covalent antibody binding, and C1BP-FEK functionalized with the collagen-binding peptide TKKTLRT for tumor extracellular matrix anchoring. The dual-affinity hydrogel enabled controlled antibody release, exhibiting only 40% cumulative release by Day 90 and an 8.8-fold reduction in initial diffusion rate. In proof-of-concept studies using SKOV3 tumor-bearing mice, the hydrogel carrying trastuzumab as a model therapeutic antibody enhanced local antibody retention, reduced. systemic exposure, exhibited negligible toxicity, and achieved a tumor inhibition rate of 68% This dual-affinity strategy overcomes limitations of conventional affinity-based hydrogels, providing a biocompatible and versatile platform for localized antibody therapy in oncology and other biomedical applications.
The stimulator of interferon genes (STING) pathway plays a critical role in bridging innate and adaptive antitumor immunity, representing a promising target in cancer immunotherapy. However, the clinical application of STING agonists is limited by poor pharmacokinetics, low cytosolic delivery efficiency, and immune-related adverse effects. To address these challenges, we developed STING polyproagonist nanoparticles (named GA+S@SR) by self-assembly of an amphiphilic diblock copolymer, P(OEGMA-co-GAMA)-b-PSSRMA, combined with POEGMA-b-P(DEAEMA-co-BMA). The galactose (GA) moieties enable targeted delivery to glucose transporter 1 (GLUT1) on tumor cells, facilitating cellular internalization. The P(DEAEMA-co-BMA) segments promote endosomal escape, followed by the release of the disulfide-linked SR-717 in the cytosol under reducing conditions. This leads to robust activation of the STING pathway, resulting in dendritic cell maturation, enhanced T-cell infiltration, and potent antitumor immunity. Furthermore, when combined with an αPD-L1, this polyproagonist synergistically enhances the efficacy of immune checkpoint blockade, effectively inhibiting primary and distant tumors by counteracting immune evasion. This study highlights the potential of STING polyproagonists in achieving effective cytosolic delivery of STING agonists to boost antitumor immunity and overcome current limitations associated with STING immunotherapy.
With low five-year survival estimates, poor prognosis, and high recurrence probabilities, glioma is considered one of the most intractable malignant tumors. Despite the discovery of lymphatic vascular system and immune system in the central nervous system (CNS), immune checkpoint blockade therapeutics, such as programmed death ligand 1 (PDL1, also called B7H1 or CD274) antibodies, are prevented from the CNS and glioma sites due to the existence of biological barriers including the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB). Herein, we constructed a BBB/BBTB-crossing recombinant antibody by fusing the PDL1 antibody (αPDL1) and the targeting moiety RAP22 peptide (RAP22) through a matrix metalloproteinase 2 (MMP2)-responsive cleavable linker, abbreviated as αPDL1-mRAP22. Not only was αPDL1-mRAP22 able to block PD1/PDL1 pathway, reduce T cell apoptosis, enhance T cell killing ability towards glioma cells in vitro, but also it showed higher accumulation in the glioma site, prolonged survival time, and potent immune responses as well as synergistic effects with temozolomide (TMZ) in vivo, offering a novel strategy for glioma immunotherapy.
Over the past decade, accumulating evidence supporting the efficacy of probiotics in gut microbiota modulation has spurred interest in their therapeutic potential for inflammatory bowel disease (IBD), a chronic intestinal disorder for which safer and more sustainable alternatives to conventional immunosuppressive and biologic treatments are urgently needed. Probiotics represent a promising therapeutic strategy due to their favorable biosafety profile and compatibility with daily health practices. Mechanistically, probiotics mitigate intestinal inflammation by suppressing pathogenic bacteria, modulating gut immunity and regulating microbial metabolites. However, their application is limited by low viability and poor intestinal colonization following oral administration. To address these challenges, advanced delivery strategies, including physical encapsulation, biohybrid nanocoating and chemical modifications, have been developed to enhance probiotic survival and targeted delivery. Despite these advances, current probiotic delivery systems face limitations, such as the impairment of microbial activity by surface modifications, deficiency in formulating intestinal digestion resistance strategies, lack of strategies for active colonization, and incomplete understanding of therapeutic mechanisms. By addressing these barriers, targeted and sustained research into innovative probiotic delivery systems may yield novel therapeutic approaches for IBD. This review indicates that relying solely on physical encapsulation or simple coating can no longer meet therapeutic demands. Future efforts must shift toward a functional synergy direction, developing multifunctional systems that protect probiotic viability without inhibiting their metabolic and physiological functions while integrating active colonization and targeted release. Furthermore, the review emphasizes the current incompleteness in understanding the therapeutic mechanisms of probiotics and calls for embedding mechanistic studies into the rational design of delivery systems. These insights provide a pathway for the field to move from determining whether live probiotics can be delivered to exploring how to achieve efficient, safe and functionally intact oral probiotic therapy.
Following injury, prostaglandin E2 (PGE2) drives intestinal epithelial repair by inducing revival stem cells (RSCs), which compensate for the loss of homeostatic Lgr5+ stem cells. Using intestinal organoid models, we demonstrate that melatonin potentiates the PGE2- or damage-induced RSC emergence by rewiring cellular plasticity toward a fetal-like state and sustaining pro-regenerative YAP activity, thereby enhancing overall repair capacity. To translate this finding into a therapeutic application, we developed a biohybrid heterospheroid (Mel-HS) by combining melatonin-loaded poly(lactic-co-glycolic acid) microspheres with 3D-cultured mesenchymal stem cells (MSCs), which serve as a PGE2 source. We confirmed that this biohybrid construct preserves the paracrine capacity of MSCs to secrete PGE2. Notably, Mel-HS demonstrates superior in vivo retention compared with naive 3D-MSCs, underscoring the cytoprotective effect of encapsulated melatonin in enhancing MSC viability. Furthermore, Mel-HS promoted robust RSC induction while simultaneously providing protection against inflammatory- and oxidative insults in vitro. In a colitis model, Mel-HS accelerated mucosal healing through the dual mechanisms-immunomodulation and enhanced RSC-driven repair-resulting in marked clinical improvement. Collectively, our findings highlight the therapeutic potential of enhancing endogenous regeneration with melatonin and MSCs, establishing a promising framework for next-generation biohybrid cell therapeutics in inflammatory bowel disease management.
Conventional therapy for ulcerative colitis (UC) is often limited by insufficient colonic targeting, short local retention and poor cellular drug uptake at lesion sites. Here, we develop a biomimetic colon-targeted delivery system based on an opposite pH-responsive "gating" strategy. Chrysanthemum sporopollenin (spo) microcapsules with a characteristic spiny architecture serve as the core carrier. Spo exhibits acid-induced contraction and alkali-induced expansion, with germinal apertures opening progressively as pH increases. In contrast, chitosan-butyrate complex (CBC) swells into a gel under acidic conditions but contracts and precipitates in alkaline environments. After drug loading into the spo, surface coating with CBC seals the germinal apertures, constructing an intelligent gate. In gastric fluid, the CBC layer gels and blocks apertures to prevent premature drug release. In intestinal fluid, CBC contracts and precipitates to open the gate; meanwhile, spo expands to further widen germinal apertures and facilitate drug release. The spiny morphology of spo, combined with the mucoadhesive properties of chitosan and active targeting of butyrate, collectively enhances intestinal adhesion and retention, enabling precise colonic drug release and accumulation. Mesalazine is formulated into liposomes to improve aqueous solubility and stability, which enhances cellular uptake and bioavailability, thereby exerting synergistic anti-inflammatory effects with butyric acid at inflamed sites. The chrysanthemum sporopollenin-based gated microcapsules exhibit favorable pH-responsive release, enhanced mucoadhesion and potent synergistic anti-inflammatory activity. This work provides a promising multifunctional targeted delivery strategy for UC therapy and establishes a novel, versatile design concept termed the opposite pH-responsive dual-gating mechanism, which supports the development of oral colon-targeted carriers capable of navigating complex gastrointestinal environments.
Cytoreductive surgery is the treatment protocol for colorectal cancer. Nonetheless, a major medical challenge remains to fully eliminate malignant tumor cells, along with a number of complications such as peritoneal adhesion and tumor peritoneal metastasis. The occurrence of peritoneal adhesions compromises not only the ability to do subsequent surgery, but also the efficacy of adjunct chemotherapy. More and more evidence suggest that the process of mesothelial-mesenchymal transition (MMT) influenced by transforming growth factor-β1 (TGF-β1) has a role to play in these disturbances, therefore making TGF-β1 a viable target for therapy. This study has designed a hydrogel-based physical barrier drug delivery system loaded with RNA interference technology, designated as FC@MT. The 5-fluorouracil (5-FU), which is known for its antitumor effects, was firmly linked to the FCGCM hydrogel matrix through the formation of hydrogen bonds. Meanwhile, APTES-modified mesoporous silica nanoparticle (AMSN)/TGF-β1 siRNA complexes were incorporated to facilitate the cellular uptake of siRNA and enable their escape from lysosomes. The localized co-delivery of 5-FU and TGF-β1 siRNA induces residual tumor cells killing by silencing TGF-β1 expression and reverses MMT. The combination of FC@MTs was shown to have a synergistic anti-peritoneal metastasis and anti-adhesion effects, which could be an effective strategy to enhance the clinical therapeutics of CRC.
Cancer-associated fibroblasts (CAFs) are the primary source of collagen I, which contributes to the formation of a dense tumor extracellular matrix (ECM). Non-selective targeting of collagen I through CAF inhibition may inadvertently promote tumor cell detachment and metastasis by triggering anoikis resistance. To address this, a "wandering tumor cells" strategy is proposed, combining the induction of tumor cell deadhesion with the reversal of anoikis resistance. For heterologous targeted drug delivery, thermosensitive lipids and a photosensitizer are incorporated into M1-type macrophage membranes (TMs) to enable laser-responsive activation. Based on this approach, we designed a photothermally triggered, functional macrophage membrane-camouflaged nano-cracker (TM@cP/siF-ErN) with a particle size of 162.20 ± 0.54 nm for the co-delivery of erianin (Er) and focal adhesion kinase small interfering RNA (siFAK). Er is encapsulated in anisamide (AA)-modified nanodiscs (ErN) with hydrodynamic diameter of 15.07 ± 7.24 nm to selectively inhibit collagen I synthesis in CAFs by targeting pyruvate carboxylase, thereby inducing tumor cell deadhesion. siFAK is delivered to tumor cells using cinnamaldehyde-modified polyethyleneimine (cP/siF) to formed complexes with a particle size of 98.57 ± 1.47 nm and enhance transfection efficiency, enabling effective FAK knockdown and reversal of tumor anoikis resistance. Furthermore, TMs are fragmented into debris to amplify M2-type macrophage repolarization. Experimental results show that the nano-cracker efficiently targets orthotopic 4T1 breast tumors and, upon laser-triggered detonation, releases ErN, cP/siF and M1-type macrophage membrane fragments, which collectively promote tumor anoikis by suppressing collagen I synthesis in CAFs and reversing tumor cell anoikis resistance. Moreover, it promotes the repolarization of M2-type macrophages, which synergizes with collagen I downregulation-induced infiltration of CD8⁺ T lymphocytes to enhance the antitumor immune response, collectively resulting in pronounced breast cancer suppression. This nano-cracker implements the "wandering tumor cells" strategy, offering a promising approach for improving tumor therapy and enabling heterologous targeted delivery.
Antisense oligonucleotides offer a powerful strategy for suppressing pro-inflammatory microRNAs, but efficient long-term delivery after systemic administration remains challenging. In this study, we developed a self-assembling oligoDNA-nanomicelle (OD-micelle) platform to simultaneously deliver antisense oligoDNA targeting miR-155 and curcumin, a hydrophobic anti-inflammatory agent, to the lung. The curcumin formulation (OD-micelle/Cur) can be administered intravenously and has a negatively charged surface and average particle size of ∼160 nm, supporting scavenger receptor (SR)-mediated pulmonary delivery. Fluorescence imaging and flow cytometry analyses demonstrated that cellular uptake was comparable to that of OD-micelle/PEI25k, a widely used cationic carrier standard. Hemocompatibility tests demonstrated reduced red blood cell aggregation, compared with PEI25k, indicating improved hemocompatibility without compromising delivery efficiency. Mechanistic studies supported the receptor-dependent transport of the oligoDNA corona. Pre-treatment with excess oligonucleotides reduced the cellular uptake and in vivo lung accumulation of Cy5-labeled OD-micelle/Cur. Furthermore, a RAGE antagonist peptide similarly reduced cellular uptake, suggesting the involvement of RAGE in the SR pathway. In LPS-induced acute lung injury (ALI) mice and LPS-stimulated Raw264.7 cells, the OD-micelle/Cur suppressed the inflammatory response, decreased TNF-α and IL-6 levels, and improved lung histopathology. The antisense oligoDNA corona contributed to the efficacy through miR-155 inhibition, which was confirmed by comparison with scrambled OD-micelle/Cur and increased SOCS1 expression in lung tissue. Furthermore, RAGE pathway inhibition attenuated the inflammatory response, suggesting that RAGE signaling could be an additional therapeutic mechanism. Therefore, OD-micelles are a systemically administrable, lung-targeted oligonucleotide nanoplatform with dual-mechanism anti-inflammatory activity for the treatment of ALI.
The Biopharmaceutics Classification System(BCS)serves as a foundational framework for drug development and,streamlines generic drugs approval by categorizing them based on solubility and intestinal permeability[1].
Osteoporosis is a skeletal disorder characterized by an imbalance between bone formation and resorption, which leads to progressive bone loss and increased fracture risk. While current treatments either inhibit bone resorption or stimulate bone formation, their long-term use is associated with adverse effects, necessitating alternative therapeutic approaches. In this study, we explore the use of red ginseng-derived nanovesicles (RGNVs) as a biocompatible nanotherapeutic strategy for treating osteoporosis. The RGNVs were successfully isolated and characterized, revealing a lipid bilayer structure enriched in bioactive ginsenosides and functional proteins. In vitro, RGNVs enhanced osteoblast proliferation, differentiation, and mineralization while suppressing osteoclast differentiation and bone resorption by modulating the BMP-2/Smad and MAPK signaling pathways. In an ovariectomy-induced osteoporosis mouse model, oral administration of RGNVs significantly restored bone volume and mineral density, and biodistribution studies confirmed their preferential accumulation in the bone tissue. Systemic toxicity evaluation indicated no adverse effects, supporting the safety of RGNVs for therapeutic use. These findings suggest that RGNVs regulate bone remodeling through a dual mechanism, to stimulate bone formation and inhibit bone resorption, thereby offering a promising and well-tolerated approach for osteoporosis management.
Endoplasmic reticulum stress (ERS), arising from the disruption of proteostasis within the tumor microenvironment, represents a fundamental driver of tumorigenesis, immune evasion and resistance against conventional therapies. In recent years, the precise modulation of ERS through the application of nanotechnology has emerged as a promising strategy to enhance the efficacy of cancer immunotherapy. This review provides a comprehensive analysis of the molecular mechanisms underlying ERS and discusses how engineered nanotherapeutics can selectively target the endoplasmic reticulum through approaches such as ligand conjugation, peptide modification or membrane fusion to induce sustained ERS. These nanotherapeutics initiate ERS by mechanisms including calcium ion dysregulation, overproduction of reactive oxygen species and direct activation of unfolded protein response signaling pathways. Persistent ERS subsequently facilitates immunogenic cell death by promoting the release of damage-associated molecular patterns, which enhance the maturation of dendritic cell and promote the activation of cytotoxic T lymphocytes. Moreover, combining ER-targeted nanotherapeutics with established therapeutic modalities, such as photodynamic therapy, photothermal therapy and chemodynamic therapy, has demonstrated synergistic antitumor efficacy and improved immune responses. Despite these advances, several critical challenges remain, particularly in terms of delivery efficiency, targeting specificity and systemic biocompatibility. Future research should emphasize the integration of nanotechnology with systems immunology and cancer metabolism, as well as the incorporation of artificial intelligence and single-cell omics to optimize the design and translational potential of ER-targeted nanotherapeutics. Collectively, these interdisciplinary strategies offer considerable potential to overcome therapeutic resistance and to promote the advancement of precision oncology.
Traditional Chinese medicine (TCM) has abundant medicinal resources and distinctive pharmacological properties. So, TCM presents considerable promise in clinical treatments. However, challenges such as poor bioavailability hinder broader clinical adoption of TCM. Microneedles (MNs), an innovative and minimally invasive transdermal platform, have emerged to enhance the therapeutic performance of TCM. The integration of MNs with TCM (TCM-MNs) overcomes key limitations of conventional administration routes to reach more targeted and efficient delivery. The structural and compositional diversity of TCM ingredients necessitates diverse TCM-MNs designs, especially "unification of medicines and excipients". Moreover, TCM-MNs can achieve synergistic benefits when combined with modality-specific interventions, like acupuncture. This review outlines advantages and types of TCM-MNs, according to the special structure and function of TCM components. Current applications of TCM-MNs in different diseases are also discussed. The review offers a promising foundation for the advancement and clinical translation of TCM-MNs in transdermal therapy.
Glioblastoma (GBM) is shielded by both the blood-brain barrier (BBB) and an immunosuppressive tumor microenvironment. Here, we develop a chimeric biohybrid nanovesicle (BEV-RVG29-PTX) that integrates viral tropism, bacterial vesiculation, and chemotherapeutic cytotoxicity into a single genetically programmable platform. Genetic fusion of rabies virus glycoprotein 29 (RVG29) to the AIDA1 autotransporter translocator domain enables robust, autonomous surface expression on bacterial extracellular vesicles (BEVs) without the need for chemical conjugation. The BEV-RVG29-PTX drives receptor-dependent BBB transcytosis and achieves efficient glioma accumulation. Encapsulated paclitaxel (PTX), otherwise restricted by BBB impermeability, is effectively delivered to intracranial tumors and induces reactive oxygen species-driven immunogenic cell death. Bone marrow-derived dendritic cells immune-activation experiments further confirmed an approximately 2-fold increase in CD80/CD86 activation. Synergizing with the pathogen-mimetic characteristics of BEVs, these signals also elicit an approximately 2-fold increase in intratumoral CD8⁺ T-cell infiltration, overcome immune exclusion, and achieve durable tumor control with extended survival in orthotopic GBM models. Accordingly, this virus-bacteria-drug biohybrid strategy enables targeted brain delivery while simultaneously amplifying antitumor immunity, offering a promising and translatable approach for GBM treatment.
Pseudomonas aeruginosa (P. aeruginosa) is a major pulmonary pathogen that establishes chronic infection through Psl polysaccharide-mediated adhesion and biofilm formation, while accelerating acute disease via toxin injection through the type III secretion system (T3SS) PcrV protein. Conventional small-molecule antibiotics show poor target specificity, limited biofilm penetration and insufficient toxin neutralization, thereby compromising therapeutic efficacy. Here, we developed a bioactive nano delivery system that integrates a bispecific antibody (BsAb) with a nano-antibiotic for P. aeruginosa infection. Specifically, an anti-Psl single-chain variable fragment (scFv) was linked with an anti-PcrV monoclonal antibody (mAb) to generate the BsAb, which was subsequently displayed on cellular outer membranes and harvested as nanoscale membrane vesicles displaying BsAb (BsAb-MVs). Gentamicin (Gen)-loaded poly (lactic-co-glycolic acid) nanoparticles (GNPs) were coated with BsAb-MVs to form BsAb-functionalized GNPs (BsAb-GNPs). By leveraging high-affinity recognition of bacterial surface antigens and enhanced antibiotic penetration, BsAb-GNPs showed robust bactericidal activity by precisely targeting planktonic bacteria and biofilms, imposing effective local drug concentration. Moreover, BsAb-MVs retained antibody-mediated adhesion neutralization and host-cell invasion blockade, thereby mitigating toxin-induced tissue damage. In vitro biofilm assays and a murine pneumonia model confirmed the precise targeting and potent antibacterial efficacy of BsAb-GNPs. Collectively, this antibody-antibiotic system integrated multifunctional antibody-antibiotic therapeutic strategy for biofilm-associated infections and offers immunological advantages, which may provide a scalable and translational strategy against P. aeruginosa biofilm infections.
The emergence of multidrug-resistant (MDR) bacterial infections has become a critical global health concern, driving the urgent need for innovative therapeutic strategies beyond conventional antibiotics. In this study, we developed a novel nanotherapeutic platform comprising protamine-loaded poly(N-vinyl-2-pyrrolidone)-stabilized silver nanoparticles (PVP-AgNPs) designed to enhance antimicrobial efficacy while improving biocompatibility. AgNPs were synthesized via chemical reduction using silver nitrate and sodium borohydride, with PVP serving as a stabilizing and capping agent. Protamine sulfate, a cationic antimicrobial peptide, was subsequently incorporated to exploit its strong affinity for bacterial membranes and synergistic bactericidal effects. The resulting nanoparticles exhibited spherical morphology with an average diameter of 70.96 ± 0.27 nm, a PDI of 0.25 ± 0.002, a zeta potential of +10.4 ± 0.15 mV, and a protamine loading efficiency of 66.2% ± 3.2%, indicating excellent colloidal stability and drug incorporation. In vitro antimicrobial testing demonstrated a two- to four-fold reduction in minimum inhibitory concentration values compared to blank PVP-AgNPs and free protamine, with disk diffusion assays confirming significantly enhanced activity against both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) bacteria. Furthermore, in vivo evaluation using a murine wound infection model showed effective bacterial clearance, accelerated wound closure, and improved tissue regeneration. These findings demonstrate that protamine-loaded PVP-AgNPs offer multimodal antibacterial activity, enhanced cytocompatibility, and the potential to overcome resistance mechanisms. Collectively, this work introduces a promising nanotherapeutic strategy for managing MDR infections and promoting wound healing, with significant implications for future biomedical applications.
Lung cancer is the most frequently diagnosed malignancy worldwide and remains the leading cause of cancer-related mortality. Effective treatment of immune-cold lung tumors remains particularly challenging due to poor immune activation and the off-target toxicity of conventional therapies. Here, we present a small-molecule–based self-assembled nanotheranostic micelle (FRANT) that employs cascade activation via folate receptor–mediated endocytosis and subsequent cathepsin B–specific cleavage, enabling tumor-selective near-infrared (NIR) fluorescence imaging and photodynamic therapy (PDT). FRANT maintains a serum-stable quenched state, thereby suppressing background fluorescence and minimizing off-target phototoxicity during systemic circulation. With an optimal hydrodynamic size of 13.7 nm, FRANT achieves deep tumor penetration, precise NIR fluorescence recovery, and robust singlet oxygen generation selectively in cancer cells. Importantly, FRANT-mediated PDT transformed immune-cold lung tumors by inducing immunogenic cell death and synergizing with PD-1 blockade, resulting in enhanced CD8⁺ T cell infiltration and durable tumor regression without systemic toxicity. Collectively, this study introduces a novel class of serum-stable, cascade-activated small-molecule nanotheranostics that couple diagnostic precision with immunomodulatory efficacy, offering a powerful platform for next-generation lung cancer therapy.
This review systematically examines the application of nanomaterials in adjuvant therapy for hepatocellular carcinoma (HCC) following surgical resection, with the aim of synergistically inhibiting tumor recurrence and driving functional liver regeneration via a 3R paradigm (removing residual tumor cells; remodeling the immune microenvironment; and repairing liver function). This article begins by analyzing the clinical challenges associated with treating HCC on the basis of global epidemiological data and the molecular characteristics of residual micrometastases after surgery. The concept of “precision space-time intervention" is then introduced, and the design strategies and clinical development of nanomaterials are explored, including targeting, biomimetic, sustained release and degradable designs. Furthermore, this review focuses on the postresection imbalance between tumor recurrence and tissue regeneration in the HCC microenvironment, elucidating the multiscale regulatory mechanisms of liver repair, such as cell differentiation, angiogenesis regulation, maintenance of the cellular redox balance, metabolic reprogramming, and modulation of the inflammatory microenvironment. The temporal dynamics of these mechanisms are emphasized, and the pivotal role of nanomaterials in this context is clarified. The key findings of this review indicate that a multimodal platform with nanomaterials as functional units can integrate diagnosis, hemostasis, antitumor activity and regeneration promotion, thereby overcoming the limitations of monotherapy, which cannot effectively cover the entire process of liver repair. This review breaks through the static intervention model of traditional adjuvant therapy, providing theoretical evidence for the development of multimodal sequential therapeutic nanoplatforms and outlining a clinical translation pathway from the validation of molecular mechanisms to GMP-standard production.
