Enzyme-Integrated Semiconducting Polymer Nanoplatform Remodels Physical and Metabolic Tumor Barriers for Potentiated...

Tumor microenvironment (TME)-associated physical and metabolic barriers severely limit the therapeutic efficacy of cancer nanomedicine. Dense extracellular matrix (ECM) impedes nanoparticle penetration, while lactate accumulation induces immunosuppression and reinforces stromal remodeling, leading to suboptimal treatment outcomes. Herein, we report an enzyme-integrated semiconducting polymer nanoplatform (PCLN) for synchronous remodeling of physical and metabolic tumor barriers to potentiate second near-infrared (NIR-II) photoimmunotherapy. The nanoplatform is constructed by crosslinking a pH-responsive semiconducting polymer nanoparticle (poly(aniline-co-aniline-N-propylsulfonic acid) (PSPA) with collagenase and lactate oxidase via a reactive oxygen species (ROS)-cleavable linker, enabling spatiotemporally controlled activation. Upon tumor accumulation, ROS-triggered disassembly restores enzymatic activity, leading to simultaneous ECM degradation and lactate depletion, thereby alleviating stromal and metabolic barriers. The released ultrasmall PSPA further enhances tumor penetration, while its NIR-II photothermal effect induces immunogenic cell death. This synergistic strategy effectively reprograms the TME by suppressing lactate metabolism, amplifying oxidative stress, and relieving stromal constraints. Consequently, PCLN combined with NIR-II laser irradiation achieves near-complete tumor inhibition, remodels the immunosuppressive TME, and potentiates antitumor immune responses. This work provides a versatile strategy for overcoming multiple TME barriers and establishes a programmable nanoplatform for potentiated NIR-II photoimmunotherapy.