Linkage-chemistry-regulated activation of ferrocene-functionalized poly(l-lysine) nanoplatforms for synergistic...

Chemodynamic therapy (CDT) relies on the relatively elevated levels of hydrogen peroxide (H₂O₂) in the tumor microenvironment (TME) to generate highly reactive hydroxyl radicals (·OH) in situ via Fenton or Fenton-like reactions. However, its therapeutic efficacy is often constrained by the limited intratumoral H₂O₂ availability and insufficient reaction kinetics at the catalytic centers. To overcome the above-mentioned bottlenecks, this study developed a pH-responsive ferrocene (Fc)-functionalized polymeric nanodelivery system, denoted as ImFc, based on a poly(l-lysine) (PLL) backbone, and incorporated the chemotherapeutic agent doxorubicin (DOX) as an in situ H₂O₂ amplification factor to achieve combined chemotherapy and CDT. This nanosystem remains structurally stable under physiological conditions but undergoes responsive disassembly in tumor-associated acidic environments, enabling the controlled release of Fc and DOX while activating the cationic properties of PLL to enhance its interactions with negatively charged intracellular biomolecular components. The Fe(II) center of Fc catalyzes the conversion of H₂O₂ into ·OH, thereby enhancing intracellular oxidative stress and promoting lipid peroxidation-associated damage. In vitro results demonstrated that, compared with the control system AmFc in which Fc was covalently immobilized, ImFc and its drug-loaded formulation exhibited higher levels of ·OH generation and lipid peroxide accumulation, indicating more pronounced ferroptosis-related cellular damage. In a murine orthotopic breast cancer model, ImFc showed a superior trend in tumor growth inhibition compared with AmFc, while both ImFc@DOX and AmFc@DOX further enhanced the antitumor efficacy. Collectively, this study demonstrates that the synergistic integration of pH-responsive release, activation of cationic properties, and substrate-supply amplification effectively improves the therapeutic efficiency and safety of CDT, providing a feasible design strategy for constructing efficient and controllable CDT-based combinational nanoplatforms.