Collagen-anchored cascade nanoreactors with prolonged intratumoral retention for combined cancer starvation and chemotherapy

Cancer starvation therapy mediated by glucose oxidase (GOx) has attracted considerable attention for treating advanced tumors. However, the severe systemic toxicity and poor stability of GOx limit the clinical translation of this strategy. To overcome these limitations, we construct collagen-anchored hollow nanoreactors to enhance intratumoral retention and biosafety of enzymes. Specifically, GOx and catalase (CAT) are encapsulated in tannic acid/poly(ethylenimine) crosslinked hollow nanocapsules ((GOx + CAT)@PTP) using a sacrificial templating method. Then doxorubicin hydrochloride (DOX) is absorbed on the surface of the (GOx + CAT)@PTP nanoreactors to form (GOx + CAT)@PTP@DOX nanoreactors. Because of the high affinity between the tannic acid in the nanoreactors and collagen in the tumor stroma, the nanoreactors greatly prolong the retention of GOx and CAT and reduce the systemic toxicity of GOx by preventing its escape. The catalytic cascade initiated by GOx and CAT realizes oxygen self-supply, facilitates glucose consumption, and lowers the pH in the tumor microenvironment, which induces DOX release. As a result, the (GOx + CAT)@PTP@DOX nanoreactors show excellent antitumor efficacy by combining starvation therapy and chemotherapy. Since collagen is abundant in various tissues, such as tumors, dermis, and tendons, our findings may facilitate the development of new enzyme delivery platforms with enhanced delivery efficiency, retention, and therapeutic efficacy.