Charge‐Convertible Degradable Nanocapsules for Eradication of Drug‐Resistant Large Tumors

Abstract Two major obstacles of nanomedicines in cancer therapy are the limited tumor penetrability and drug‐resistance, especially for those large tumors, severely hampering their therapeutic efficacy for clinical translation. Here, a charge‐convertible degradable silica nanocapsule co‐packaging doxorubicin (DOX) and P‐ glycoprotein siRNA (siPgp) (DOX‐siPgp@Cap ⊖ ) that can penetrate throughout the entire tumors and suppress Pgp protein expression for effective drug‐resistant cancer therapy of large tumors is reported. When sensing the tumor acidity, the DOX‐siPgp@Cap ⊖ undergoes negative‐to‐positive charge‐reversal and triggers cationization‐mediated transcytosis for efficient co‐delivery of DOX and siPgp into the deep tumor sites, achieving high cellular uptake efficiency and deep tumor penetration. The DOX‐siPgp@Cap ⊖ is degradable in acidic lysosomes, leading to sustainable releases of siPgp and DOX and their subsequent escape from lysosomes. Evidently, the DOX‐siPgp@Cap ⊖ displays the superior deep tumor penetration capability, and concomitantly suppresses Pgp expression in tumor tissues, thereby significantly reducing DOX resistance. In vivo studies demonstrate the exceptional therapeutic efficacy of the DOX‐siPgp@Cap ⊖ in drug‐resistant triple‐negative breast cancer mouse models that leads to the eradication of clinically large tumors (≈500 mm 3 ) with significantly extended survival. This study provides a promising solution for maximizing the therapeutic benefits of nanomedicines in drug‐resistant cancer therapy.