Aug 2026· Journal of the American Chemical Society· 0 citations· 49 references
TL;DR
Overall, this multifunctional nanomotor couples enhanced drug delivery with immune activation, effectively overcoming the structural and metabolic barriers of solid tumors, and represents a promising strategy for self-propelled therapeutic nanoparticles in cancer treatment.
Abstract
Solid tumors present a therapeutic challenge due to their dense extracellular matrix and metabolically immunosuppressive microenvironment, which limit drug penetration and immune clearance. To overcome these barriers, we describe an engineered lactate-powered Janus nanomotor (NM(dox)-LOx) composed of a platinum (Pt) nanodendrite and a mesoporous silica nanoparticle (MSN), loaded with doxorubicin (Dox) and functionalized with the enzyme lactate oxidase (LOx). In this design, LOx acts as a protease-sensitive molecular gate for controlled Dox release and catalyzes the oxidation of tumor-accumulated lactate, using this metabolite as a biofuel to generate hydrogen peroxide, which is catalyzed by Pt into oxygen and water. This cascade generates a self-propulsive force that drives the nanomotor. Concurrently, catalytic lactate depletion reprograms the tumor microenvironment, promoting cytotoxic T cell infiltration and restoring immune activity. NM(dox)-LOx demonstrates efficient tumor accumulation and potent antitumor activity in human SK-MEL-103 and murine B16–F10 melanoma models, including 2D cultures, 3D spheroids, and in vivo tumors. Remarkably, treatment in an in vivo B16–F10 melanoma model achieved pronounced tumor regression and enhanced cytotoxic T cell infiltration, while maintaining minimal systemic toxicity. Overall, this multifunctional nanomotor couples enhanced drug delivery with immune activation, effectively overcoming the structural and metabolic barriers of solid tumors, and represents a promising strategy for self-propelled therapeutic nanoparticles in cancer treatment.
A biodegradable biomimetic nanoplatform (HMCDL@TK-M) was constructed by combining hydrogen-doped HxMoO3 nanoparticles, dual-drug loading, and a hybrid spinach-cancer cell membrane coating. The system features pH-responsive biodegradability, tumor-homing capability, and high NIR-II photothermal conversion. An oxygen-lactate cascade, formed via thylakoid membrane-mediated H2O2 decomposition and lactate oxidase-driven lactate oxidation, alleviates hypoxia and depletes lactate in the tumor microenvironment. This dual metabolic modulation reprograms M2 macrophages to M1, promotes dendritic cell maturation, and reduces Treg infiltration. In 4T1 tumor-bearing mice, HMCDL@TK-M achieves strong tumor accumulation, effective photothermal ablation, and combined with lactate depletion, complete tumor eradication without systemic toxicity. The treatment also induces robust CD4+/CD8+ effector memory T-cell responses, providing durable antitumor immunity. This work demonstrates a synergistic metabolic-photothermal immunotherapy strategy for efficient and long-lasting cancer treatment.
Shuo Gao, Yu Chen, Yan-Xi He et al.· Advanced Healthcare Material...· 0 citations
BIMLM is developed as a biomimetic nanoplatform integrating lactate oxidase (LOX)-driven lactate exhaustion with MnO2-coated IR-780 for TME remodeling and self-amplifying ROS generation that enhances PDT/CDT efficacy while triggering metabolic starvation and ferroptosis, which collectively enable tumor eradication.
Boye Zhang, Yuli Chen, Pengyan Qiao et al.· Journal of Advanced Research· 0 citations
Microbiome and transcriptome analyses revealed that Fusobacterium nucleatum (F.n) in clinical samples is associated with immune suppression and poor prognosis in triple-negative breast cancer spinal metastasis. However, its preferential localization in hypoxic tumor regions limits the efficacy of conventional antimicrobial therapies, which poorly penetrate solid tumors and function suboptimally under anaerobic conditions. Developing strategies that enable deep tumor penetration, eliminate anaerobic bacteria, and induce immunogenic cell death remains a major challenge. In this study, a novel charge-enrichment and light-activated biomimetic nanosystem, designated as polyion liquid-bridged eosin Y (PIL-BEY), was developed. On one hand, interionic hydrogen bonding and dynamic electrostatic interactions within polyionic liquids reduce the surface energy of the nanoprobe and synergistically remodel the dense tumor stromal microenvironment via photodynamic therapy, thereby facilitating the deep intratumoral penetration and accumulation of PIL-BEY. On the other hand, the novel photosensitizer BEY generates reactive oxygen species via electron transfer under hypoxic conditions, thereby effectively eradicating bacteria within hypoxic tumor regions. The resulting pathogen-associated molecular patterns, together with damage-associated molecular patterns, activate dendritic cells, promote cytotoxic T lymphocyte infiltration, trigger immunogenic cell death, and induce systemic antitumor immune responses with durable immune memory. This oxygen-independent, dual-functional nanoplatform offers a promising strategy for treating invasive metastatic tumors.
Chao Jia, Hongwei Lu, Jinjin Wang et al.· Journal of Nanobiotechnology· 0 citations
Hypoxia, immunosuppression, and pronounced heterogeneity within the tumor microenvironment (TME) hinder the effectiveness of cancer therapies. Engineered bacteria–nanomaterial hybrid systems have emerged as a promising approach to address these challenges. Bacterial chassis provide active tumor targeting, deep tissue penetration, and in situ proliferation, facilitating the precise delivery of immunomodulators. Concurrently, nanomaterials interfaced with these living carriers can be activated by external physical stimuli, inducing photothermal, photodynamic, sonodynamic, and magnetothermal effects within solid tumors. These interactions promote immunogenic cell death (ICD) and enable real-time monitoring. Recent advances in synthetic biology and nanotechnology have led to the development of an expanding range of preclinical biohybrid platforms, while several related components, including bacterial therapeutics, bacterial derivatives, and physically activated nanomedicine platforms, have progressed into clinical evaluation. This review first explores the origins and roles of tumor-associated bacteria. It then summarizes strategies for engineering bacteria–nanomaterial hybrid systems. Subsequently, this review examines how physical stimuli enhance targeting, remodel the TME, and amplify antitumor immunity. Finally, safety, manufacturing, and regulatory challenges impacting clinical translation are discussed. Overall, these platforms offer a potentially powerful framework for precision cancer immunotherapy. However, successful clinical translation will require stronger evidence regarding safety, controllability, manufacturing consistency, and therapeutic efficacy.
Jiayue Lin, Ming An, Yuxin Dai et al.· Research· 0 citations
BackgroundSonodynamic therapy (SDT) has emerged as a promising strategy for cancer treatment; however, its therapeutic efficacy is significantly limited by the hypoxic tumor microenvironment, particularly in breast cancer. To address this limitation, we developed a biomimetic nanoplatform capable of generating oxygen within the tumor microenvironment to enhance SDT performance.MethodsPoly (lactic-co-glycolic acid) (PLGA) nanoparticles were co-loaded with catalase and the sonosensitizer IR780 and subsequently coated with 4T1 cancer cell membranes (CIP@4T1m NPs). A series of in vitro and in vivo experiments were conducted to evaluate tumor-targeting capability, hypoxia alleviation, singlet oxygen (1O2) generation, antitumor efficacy, induction of immunogenic cell death (ICD), and activation of antitumor immune responses.ResultsThe resulting CIP@4T1m NPs were successfully fabricated and exhibited preferential accumulation in 4T1 tumor cells and orthotopic 4T1 tumor-bearing mice. Both in vitro and in vivo studies demonstrated that the nanoplatform partially relieved tumor hypoxia and significantly enhanced SDT-mediated 1O2 production and antitumor effects. Moreover, CIP@4T1m NPs combined with ultrasound induced ICD-associated changes, promoted dendritic cell maturation, facilitated the polarization of tumor-associated macrophages from the M2 to M1 phenotype, reduced regulatory T cell populations, and increased intratumoral CD8+T-cell infiltration.ConclusionThis work describes a biomimetic nanoplatform that integrates homologous targeting with enzymatic oxygen generation to enhance SDT efficacy and promote antitumor immune responses in an orthotopic 4T1 breast cancer model. The proposed strategy offers a potential approach to mitigate hypoxia-associated limitations in cancer therapy.
Haiqin Liao, Shiyu Ding, Ming Zhang et al.· Journal of Applied Biomateri...· 0 citations
Metastatic melanoma remains a critical clinical challenge due to high transcriptional plasticity and the physical barriers of the tumor microenvironment that limit the efficacy of standard therapies. In this study, we present a microfluidic-engineered poly(lactic-co-glycolic acid) nanoparticle (PLGA-NPs) platform designed to maximize therapeutic efficacy through the precise co-encapsulation of synergistic drug combinations. These monodisperse nanocarriers exhibit rapid, dose-dependent internalization across diverse patient-derived models, independent of their mutational background. Mechanistically, we demonstrate that PLGA-NPs uptake is primarily mediated by dynamin-dependent endocytosis and macropinocytosis, followed by a dynamic intracellular trafficking route that reaches a steady-state distribution within recycling endosomes, thereby enabling prolonged intracellular cargo retention. In 3D patient-derived spheroids, these nanoparticles exploit active cell-to-cell transfer consistent with transcytosis-like mechanism to penetrate the poorly accessible central core, effectively bypassing tissue-level resistance and considerably enhancing drug efficacy. In vivo biodistribution in orthotopically transplanted patient-derived xenografts confirmed highly efficient tumor targeting, while a strategic dose-modulation approach successfully optimized the tumor-to-liver accumulation ratio. Therapeutically, twice-weekly intravenous administration of trametinib-loaded NPs achieved superior tumor regression and significantly prolonged overall survival compared to daily oral administration of the free drug. Furthermore, we developed a dual-drug delivery system co-loading trametinib, MEK inhibitor, and alisertib, Aurora A kinase inhibitor. This formulation was optimized to maintain a previously established synergistic ratio which effectively overcome acquired resistance to standard-of-care therapies and induce durable tumor regression. Collectively, these findings establish the PLGA-NPs platform as a robust, clinically relevant strategy to enhance the pharmacokinetic profile of treatments for metastatic and drug-resistant melanoma.
Giulia Lovati, Pietro Milesi, Paolo Fossati et al.· Journal of Controlled Releas...· 0 citations
