pH-Independent charge-reversal strategy for enhanced tumor penetration based on hyaluronidase-responsive tellurium-containing polycarbonate nanocarriers

The charge-reversal strategy has been of great significance for enhancing the penetration of nanomedicines in tumors. However, conventional charge reversal has always been confined to pH variation. Herein, we proposed a pH-independent charge-reversal strategy based on hyaluronidase-responsive polycarbonate nanocarriers bearing quaternary ammonium groups. We developed multifunctional polycarbonate-based nanocarriers using tellurium/quaternary ammonium-containing carbonate copolymers. The encapsulation of cisplatin was achieved through coordination complexation with tellurium atoms. The positive charge was shielded from the circulation <i>in vivo</i> by the modification of hyaluronic acid and then exposed in HAase. <i>In vitro</i> cell experiments confirmed the selective killing effect of the drug carriers on pancreatic tumor cells and revealed a mitochondria-targeted pro-apoptotic mechanism. <i>In vivo</i> animal experiments verified the anti-tumor ability and significant tumor tissue penetration ability of the drug carriers. Therefore, the proposed pH-independent deep-tumor-penetration nanocarriers provide a potential nanoplatform for the stable clinical treatment of dense solid tumors.