Tumor Microenvironment‐responsive Nanocatalyst for Targeted Chemodynamic Cancer Therapy

To address the challenges of insufficient hydrogen peroxide (H₂O₂) levels, rapid Fe³⁺ 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 H₂O₂ levels (50-100 µm). H₂O₂ triggered the degradation of PLGA, releasing CaFe clusters to produce Fe³⁺/Fe²⁺ and additional H₂O₂, sustaining the Fenton reaction. Simultaneously, polyarginine releases nitric oxide (NO) in the presence of H₂O₂, facilitating Fe³⁺ reduction to Fe²⁺ 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.