An intelligent responsive ZIF-8 co-delivery nanoplatform with multimodal synergistic technologies for closed-loop therapy of tumors

Multi-modal combination therapy for tumors can overcome the limitations of single-modal therapy and bring new opportunities for high-efficient tumor treatment. Nevertheless, how to ingeniously design functionalized nanocarriers to mediate the synergistict effects among various therapeutic approaches remains a core challenge. In this study, we developed a polydopamine (PDA) coated outside and glucose oxidase (GOx) adsorbed inside copper-doped zeolitic imidazolate framework-8 (CZ8) with metformin hydrochloride (MET) / doxorubicin (DOX) as a multifunctional nano-codelivery system, abbreviated as PMDGCZ8, which could focus more on the synergy and continuity of multiple therapies including photothermal therapy (PTT), chemodynamic therapy (CDT), starving tumor therapy (STT) and chemotherapy (CT). Herein, PMDGCZ8 innovatively combined the gating effect of PDA membrane with the pH sensitivity of CZ8 skeleton to form a dual-responsive bomb that could trigger release on demand and significantly improve the accuracy of tumor localization. Furthermore, we also incorporated the strategies of reshaping the tumor hypoxia and immunosuppressive microenvironment into the synergistic treatment process in order to achieve a comprehensive anti-tumor ecological network. Both in vitro and in vivo experiments suggested that PMDGCZ8 significantly enhanced drug accumulation on tumors, reduced systemic toxicity, activated anti-tumor immune response, further inhibited the recurrence and metastasis, and consequently was expected to become a new type of nano-delivery platform with great development potential.