A Sequential Target‐Responsive Nanocarrier with Enhanced Tumor Penetration and Neighboring Effect In Vivo

Nanodrug‐based cancer therapy is impeded by poor penetration into deep tumor tissues mainly due to the overexpression of hyaluronic acid (HA) in the tumor extracellular matrix (ECM). Although modification of nanoparticles (NPs) with hyaluronidase (HAase) is a potent strategy, it remains challenging to get a uniform distribution of drug at the tumor site because of the internalization of NPs by the cells in the tumor and HA regeneration. Herein, an intelligent nanocarrier, which can release HAase in response to the acidic tumor microenvironment (pH 6.5) and perform a strong neighboring effect with size reduction to overcome the above two problems and accomplish drug deep tumor penetration in vivo, is reported. In this design, HAase is encapsulated on the surfaces of doxorubicin (DOX) preloaded ZnO‐DOX NPs using a charge convertible polymer PEG‐PAH‐DMMA (ZDHD). The polymer can release HAase to degrade HA in the tumor ECM (pH 6.5). ZnO‐DOX NPs can release DOX in lysosomes (pH 4.5) to induce cell apoptosis, and exert a neighboring effect with size reduction to infect neighboring cells. The hierarchical targeted release of HAase and drugs is demonstrated to enhance tumor penetration and decrease side effects in vivo. This work shows promise for further application of ZDHD NPs in cancer therapy. An intelligent nanocarrier, which combines acidic tumor microenvironment‐responsive hyaluronidase (HAase) release and remarkable neighboring effect with size reduction, is envisaged. The released HAase can efficiently decompose excessive hyaluronic acid (HA) in the extracellular matrix, improving the diffusion of nanodrugs. Additionally, the integration of HAase and neighboring effect with size reduction can overcome the problem of HA regeneration, and enhance tumor penetration and the antitumor effect.