Piezoelectricity-Potentiated Bioorthogonal Catalysis Disrupts Cholesterol Metabolism for Tumor Immunotherapy

Cholesterol metabolism plays a pivotal role in cancer progression and immune evasion. However, the adverse side effects of cholesterol-lowering medications, resulting from off-target activity and high-dose requirements, represent a serious bottleneck in current clinical application strategies. Here, we report a bioorthogonal catalytic system (FA-BSI@HOFe NCs) potentiated by the pyroelectric effect of a piezoelectric material. This system is constructed by integrating a hydrogen-bonded organic framework (HOF) catalyst with piezoelectric material (Bi₁₃S₁₈I₂ nanorods, BSI NRs), to modulate tumor cholesterol metabolism for immunotherapy. The introduction of piezoelectric BSI NRs leverages their pyroelectric properties to generate electron–hole pairs upon temperature fluctuation and also exhibits potent photothermal conversion. This synergy creates an electron-rich, heated microenvironment that significantly promotes HOF-catalyzed bioorthogonal prodrug activation. Consequently, the activated prodrug suppresses cholesterol biosynthesis, inhibiting tumor growth and reinvigorating antitumor immunity. This targeted bioorthogonal system activates drug activity in situ, maximizing therapeutic efficacy while minimizing off-target toxicity. Our work will broaden strategies for regulating cholesterol metabolism and provide insights into the design of highly efficient bioorthogonal catalysts.