A pH-responsive metal-phenolic nanoplatform for integrated chemosensitization and cardioprotection via dual AKR1C3/survivin inhibition

Abstract The clinical utility of doxorubicin (DOX) is significantly hindered by potent cardiotoxicity and the emergence of drug resistance. To circumvent these limitations, we engineered a multifunctional, self-assembled coordination nanoplatform-DOX/DMY-Fe ³⁺ @PEG nanoparticles (DDFP NPs)-driven by the metal-phenolic coordination between Fe ³⁺ , DOX, dihydromyricetin (DMY), and polyethylene glycol (PEG)-polyphenols. The resulting DDFP NPs exhibited high drug-loading capacity, robust colloidal stability, and a distinct pH-responsive release profile. Furthermore, the nanoplatform demonstrated a significantly prolonged systemic half-life, which facilitated preferential accumulation within the tumor microenvironment via the enhanced permeability and retention effect. In vitro investigations revealed that DDFP NPs efficiently internalized into U87MG glioma cells, where the co-delivered DMY and DOX synergistically downregulated the expression of aldo-keto reductase family 1 member C3 (AKR1C3) and Survivin. This dual-target reduction not only sensitized tumor cells to DOX-induced apoptosis but also potentially suppressed the bioreduction of DOX into its cardiotoxic metabolite, doxorubicinol (DOXOL). In vivo evaluations in U87MG xenograft models confirmed that DDFP NPs achieved superior antitumor efficacy while markedly alleviating DOX-associated myocardial damage. Collectively, this study establishes a robust nano-strategy that integrates chemosensitization and attenuation of acute cardiotoxicity through a rationally designed coordination system, offering significant potential for clinical translation in anthracycline-based cancer therapy.