A Nanoplatform to Amplify Apoptosis-to-Pyroptosis Immunotherapy via Immunomodulation of Myeloid-Derived Suppressor Cells

• Published in: ACS applied materials & interfaces 2021-10, Vol.13 (40), p.47407-47417
• Main Authors: Zhou, Shiyao, Shang, Qi, Ji, Jianbo, Luan, Yuxia
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Biological and Medical Applications of Materials and Interfaces; Cell Line, Tumor; Drug Carriers - chemistry; Drug Liberation; Female; Hyaluronic Acid - chemistry; Hydralazine - chemistry; Hydralazine - therapeutic use; Imidazoles - chemistry; Immunologic Factors - chemistry; Immunologic Factors - therapeutic use; Immunomodulation - drug effects; Immunotherapy - methods; Metal-Organic Frameworks - chemistry; Mice; Mice, Inbred BALB C; Mitoxantrone - chemistry; Mitoxantrone - therapeutic use; Myeloid-Derived Suppressor Cells - drug effects; Nanoparticles - chemistry; Neoplasm Metastasis - prevention & control; Neoplasms - drug therapy; Proof of Concept Study; Pyroptosis - drug effects
• ISSN: 1944-8244; 1944-8252
• DOI: 10.1021/acsami.1c16154

Pyroptosis is a programmed cell death to enhance immunogenicity of tumor cells, but pyroptosis-based immunotherapy is limited due to the immune escape involving myeloid-derived suppressor cells (MDSCs). Therefore, designing a nanoplatform to not only trigger apoptosis-pyroptosis transformation but also combat the MDSC-based immune escape is of great significance. As a proof-of-concept study, here, we designed a metal organic framework (MOF)-based nanoplatform to tailor the pyroptosis immunotherapy through disrupting the MDSC-mediated immunosuppression. By pH-responsive zeolitic imidazolate framework-8 (ZIF-8) modified with hyaluronic acid (HA), the chemotherapeutic drug mitoxantrone (MIT) and DNA demethylating agent hydralazine (HYD) were successfully co-encapsulated into ZIF-8 for achieving (M+H)@ZIF/HA nanoparticles. This nanoplatform demonstrated a powerful apoptosis-to-pyroptosis transformation with a potent disruption of MDSC-mediated T cell paralysis via reducing immunosuppressive methylglyoxal by HYD. Overall, our two-pronged nanoplatform (M+H)@ZIF/HA can switch the cold tumor into an arsenal of antigens that stimulate robust immunological responses, while suppressing immune escape, collectively triggering vigorous cytotoxic T cell responses with remarkable tumor elimination and building a long-term immune memory response against metastasis.