Tumor Microenvironment‐responsive Nanocatalyst for Targeted Chemodynamic Cancer Therapy

Abstract To address the challenges of insufficient hydrogen peroxide (H 2 O 2 ) levels, rapid Fe 3+ precipitation, and a slow Fenton reaction cycle, tumor‐activated, self‐accelerating CDT nanocatalysts are synthesized, comprising poly (lactic‐co‐glycolic acid) (PLGA)‐encapsulated Ca‐Fe peroxide clusters and polyarginine (R). Nanocatalysts are camouflaged with cancer cell membranes (CCM) to enhance tumor targeting. Additionally, polyarginine tailored the PLGA responsiveness to low H 2 O 2 levels (50–100 µ m ). H 2 O 2 triggered the degradation of PLGA, releasing CaFe clusters to produce Fe 3+ /Fe 2+ and additional H 2 O 2 , sustaining the Fenton reaction. Simultaneously, polyarginine releases nitric oxide (NO) in the presence of H 2 O 2 , facilitating Fe 3+ reduction to Fe 2+ and amplifying •OH generation. In vitro cellular studies demonstrate significantly improved homotypic tumor targeting (6.5‐fold increase) and deep spheroid penetration (>120 µm), resulting in improved tumor permeability and elevated •OH generation. Additionally, the nanoparticles exhibit dose‐dependent cytotoxicity, and polyarginine notably enhanced the cytotoxicity of CCM‐PLGA‐CaFe NPs, reducing the IC50 value from 216.9 to 43.38 µg mL −1 . Apoptosis/necrosis assay reveals that the elevated •OH generation by CCM‐PLGA‐CaFe‐R NPs preferentially induced necrosis, effectively inhibiting tumor cell proliferation by 76.3% ± 8.4% over a 7‐day treatment. Consequently, this TME‐responsive, self‐accelerating CDT platform demonstrates enhanced therapeutic efficacy through improved tumor targeting, sustained Fenton reaction, and amplified radical generation.