Yang Liu

Radiotherapy (RT) efficacy is often limited by two key challenges: rapid restoration of tumor genomic integrity through DNA repair and the lack of tumor‐confined radiosensitization. Although existing radiosensitizers can enhance initial DNA damage, they generally fail to suppress subsequent self‐repair of tumor cells and often induce off‐target toxicity due to nonspecific activation. Here, we report a hydrated electron ()‐activated nano‐radiosensitizer (RT‐nRS) that enables tumor‐confined radiosensitization by converting transient RT‐induced damage into persistent subcellular dysfunction. Unlike conventional RT‐responsive systems that rely on short‐lived reactive oxygen species, RT‐nRS leverages the longer lifetime of to trigger the irradiation‐induced zwitterion‐to‐cationic surface transformation, thereby maintaining systemic circulation stability while enhancing tumor cellular internalization. Furthermore, preferential accumulation and prolonged retention within the endoplasmic reticulum (ER) enable RT‐nRS to induce sustained ER stress, thereby simultaneously amplifying DNA damage and suppressing DNA repair. Our results demonstrate that RT‐nRS effectively overcomes tumor radioresistance while minimizing off‐target toxicity to non‐irradiated normal tissues, leading to significantly enhanced radiotherapy efficacy. Our work establishes hydrated electron‐responsive chemistry as a strategy for spatiotemporally controlled radiosensitization and provides a general framework for converting transient radiotherapeutic stimuli into durable biological outcomes.

Radiotherapy (RT) efficacy is often limited by two key challenges: rapid restoration of tumor genomic integrity through DNA repair and the lack of tumor‐confined radiosensitization. Although existing radiosensitizers can enhance initial DNA damage, they generally fail to suppress subsequent self‐repair of tumor cells and often induce off‐target toxicity due to nonspecific activation. Here, we report a hydrated electron ()‐activated nano‐radiosensitizer (RT‐nRS) that enables tumor‐confined radiosensitization by converting transient RT‐induced damage into persistent subcellular dysfunction. Unlike conventional RT‐responsive systems that rely on short‐lived reactive oxygen species, RT‐nRS leverages the longer lifetime of to trigger the irradiation‐induced zwitterion‐to‐cationic surface transformation, thereby maintaining systemic circulation stability while enhancing tumor cellular internalization. Furthermore, preferential accumulation and prolonged retention within the endoplasmic reticulum (ER) enable RT‐nRS to induce sustained ER stress, thereby simultaneously amplifying DNA damage and suppressing DNA repair. Our results demonstrate that RT‐nRS effectively overcomes tumor radioresistance while minimizing off‐target toxicity to non‐irradiated normal tissues, leading to significantly enhanced radiotherapy efficacy. Our work establishes hydrated electron‐responsive chemistry as a strategy for spatiotemporally controlled radiosensitization and provides a general framework for converting transient radiotherapeutic stimuli into durable biological outcomes.

Target protein degradation (TPD) represents an innovative therapeutic strategy with promising prospects for treating diseases driven by many undruggable protein targets. Recently, a variety of small-molecule protein degraders have shown promising therapeutic efficacy. However, several intrinsic limitations of these compounds impede their broader clinical translation. Meanwhile, advances in nanomaterials provide a versatile and powerful platform to overcome these challenges for advancing protein degradation technology. This review systematically summarizes the progress and prospects of nanoparticle-based TPD strategies. First, we critically evaluate the limitations of existing small-molecule protein degraders. We then outline the fundamental design principles that govern nano-enabled protein degradation systems and discuss how nanotechnology can address key challenges associated with delivery, selectivity, and controllability. We further highlight the distinctive properties of major nanomaterial platforms and their therapeutic applications in targeted protein degradation. Finally, we discuss the remaining obstacles and future directions for translating nano-protein degraders into clinically viable therapies. In conclusion, this review aims to provide both theoretical insights and practical guidance to propel the rational design and advanced application of TPD research.

Lung cancer imposes the highest cancer‐related mortality burden worldwide, while its responsiveness to immunotherapy is often constrained by the immunosuppressive pulmonary tumor microenvironment (TME) and tumor adaptations that buffer oxidative stress. Pyroptosis, a highly immunogenic form of programmed cell death that can be activated through mechanisms not strictly dependent on exogenous reactive oxygen species (ROS), offers a promising alternative for immune activation but remains challenging to induce effectively in vivo. Here, we report an inhalable fluorinated polymer nanoplatform (PFAP) that triggers mitochondrial dysfunction to initiate pyroptosis and thereby elicits potent antitumor immunity in the lung. PFAP integrates perfluoroalkyl segments with cationic domains to enhance interactions with mitochondrial membranes, while a detachable polyethylene glycol shell preserves nanoparticle stability during aerosolization and facilitates penetration of pulmonary barriers. Upon exposure to the acidic TME, PFAP restores membrane‐disruptive activity, leading to mitochondrial depolarization, Cyto C release, caspase‐3 activation, GSDME cleavage, and pyroptosis induction. In orthotopic and metastatic lung cancer models, inhaled PFAP achieves efficient lung delivery, elicits robust antitumor immunity, and suppresses tumor progression without detectable systemic toxicity. This work provides a nanomaterial‐based approach for inducing pyroptosis in lung cancer and highlights the potential of inhalable polymer systems for localized cancer immunotherapy.

Targeted protein degradation (TPD) has fundamentally redefined pharmacological intervention, shifting from classical occupancy‐driven inhibition to event‐driven elimination of undruggable pathogenic proteins, holding great promise for treating various intractable diseases. Although heterobifunctional degraders and molecular glues show immense therapeutic promise, their clinical translation is hindered by pharmacokinetic and pharmacodynamic disconnects, including violation of Lipinski's Rule of Five (Ro5) and autoinhibitory thermodynamics known as the hook effect. Nanoparticle‐based delivery systems offer a feasible solution that goes beyond passive solubilization. This review provides a comprehensive evaluation of advanced nanocarriers as spatiotemporal kinetic orchestrators, highlighting their capacity for active and precise therapeutic applications. In this review, we summarize recent progress in nanoparticle‐based TPD delivery strategies, outlining TPD molecular pathways and diverse nanocarriers for efficient delivery of TPD agents, including liposomes, polymeric nanoparticles, micelles, DNA nanostructures, inorganic nanomaterials, and biological carriers. Furthermore, the mechanisms, targeting strategies, preclinical efficacy, biological barriers, and optimization strategies of these works are detailed. Finally, we propose two solutions, namely localized zero‐order release platforms and engineered living vectors, with the potential to bypass physiological barriers and promote the clinical translation of TPD.

Employing neutrophils (NEs) as endogenous moving gears offers a promising strategy for crossing the blood–brain barrier (BBB) in the treatment of central nervous system (CNS) malignancies such as glioblastoma (GBM). However, in vivo hitchhiking efficiency of NEs is severely limited by spontaneous formation of a nonspecific protein corona. Here, we present pathogen‐mimetic liposomes (PM‐Lipo) that enable efficient and precise NEs hitchhiking by programming the in vivo protein corona. PM‐Lipo is rationally engineered to preferentially enrich complement 3b (C3b) and inactivated C3b (iC3b), thereby recapitulating endogenous complement opsonization and promoting complement receptor 3 (CR3)‐mediated recognition by activated NEs. This effect arises from the synergistic integration of two functional lipids that activate distinct complement pathways, triggering a proteolytic cascade with positive feedback to amplify C3b/iC3b deposition. Our results demonstrate that PM‐Lipo achieved >85% targeting efficiency toward activated NEs, enabling hitchhiking‐mediated transport across the BBB, with 8.94% of the administered PM‐Lipo successfully penetrating the brain, leading to marked tumor suppression and more than a twofold extension in median survival. Our research establishes a protein corona programming strategy to harness endogenous immune cells for targeted drug delivery, offering a broadly applicable paradigm for precision nanomedicine in CNS malignancies.

Engineered bacteria have emerged as a promising therapeutic modality but face safety risks and delivery challenges in clinical practice. Herein, we develop a programmable encapsulation technology that formulates individual bacteria with a thin formulation layer of cross‐linked polymers, which confers live bacteria with reduced immunogenicity and restricted proliferation in healthy organs. To leverage these benefits, an engineered Escherichia coli Nissle strain capable of converting tumor‐accumulated ammonia into L‐arginine and secreting soluble programmed cell death protein 1 (sPD‐1) was encapsulated to synthesize a degradable bacterial capsule, optimizing both biosafety and delivery processes while preserving therapeutic function. Upon reaching the tumors, matrix metalloproteinase‐2 triggers bacterial release and local proliferation, achieving L‐arginine‐driven tumor immune microenvironment modulation and sustained PD‐L1 blockade, ultimately initiating robust antitumor immune responses. Overall, this programmable encapsulation platform tackles both safety risks and delivery challenges of bacterial medicines, broadening the clinical application prospects of live bacterial therapeutics.

Pyroptosis is a highly immunogenic form of programmed cell death with great potential for cancer immunotherapy. However, achieving tumor-selective and intrinsically controllable induction of pyroptosis remains challenging. Here, we report a nanoparticle-based mitochondrial disruptor, termed nanoMd/PA, which acts as an intrinsic pyroptosis inducer by directly destabilizing mitochondrial membranes in tumor cells. Inspired by the membranolytic activity of antimicrobial peptides, nanoMd/PA is engineered with a guanidinium-rich shell that selectively accumulates in tumor mitochondria and disrupts membrane integrity through a pore-forming mechanism, thereby initiating gasdermin-mediated pyroptosis. The nanoparticle is further shielded with a pH-responsive polymer layer that remains inert during circulation but activates its mitochondrial-lytic function specifically within the acidic tumor microenvironment. In an orthotopic colorectal cancer model, nanoMd/PA treatment triggers robust pyroptosis, resulting in significant tumor suppression, extended survival, and potent inhibition of metastatic spread, all without detectable systemic toxicity. This work establishes a carrier-independent, nanomaterial-driven approach to induce pyroptosis through direct mitochondrial membrane disruption, offering a new paradigm for activating antitumor immunity with synthetic, intrinsically immunomodulatory nanoparticles.

Cancer immunotherapy has revolutionized oncology by harnessing the immune system to eliminate malignant cells, yet its efficacy remains constrained by insufficient antigen presentation, limited T cell infiltration, and the immunosuppressive tumor microenvironment (TME). Nanotechnology provides strategies to address these barriers by enabling the precise delivery of antigens, adjuvants, cytokines, checkpoint inhibitors, and nucleic acids, while protecting labile cargos and allowing for controlled release. Beyond serving as carriers, nanoparticles can regulate antitumor immunity by enhancing antigen presentation, promoting T cell priming and infiltration, and remodeling the TME. This review outlines key physiological barriers to in vivo nanoparticle delivery and the corresponding engineering optimization strategies, and systematically summarizes representative advances in using nanomaterials to enhance antigen presentation, promote T cell priming and intratumoral infiltration, and remodel the tumor microenvironment. We further discuss major translational limitations, including heterogeneous tumor accumulation, intracellular trafficking bottlenecks, safety considerations, and manufacturing consistency, and finally highlight the realizable potential of nano-immunotherapy to improve both the efficacy and specificity of cancer immunotherapy.