Manganese-based microcrystals equipped with Ythdf1-targeted biomimetic nanovaccines for reinforced dendritic cell spatiotemporal orchestration

Abstract

Undesired dendritic cell (DC) spatiotemporal orchestration and innate immune stimulation severely dampens anti-tumor efficacy of cancer vaccines. Here, we develop a manganese-based (Mn2+) metal-organic framework (MOF) microcrystal equipped with Ythdf1-targeted biomimetic nanovaccines to create an in situ proinflammatory immune niche for augmented DC spatiotemporal orchestration. The bimetallic MOF microcrystal serves as a self-adjuvanting delivery platform that cannot only gradually release tumor-associated antigens and Mn2+, but also create an in situ immune niche for DC spatiotemporal orchestration including recruitment (particularly for DC1s, cross-presenting antigens to CD8+ T cells), activation, and lymph node migration. Benefitting from the Mn2+-mediated cGAS-STING activation together with Ythdf1 downregulation-induced antigen cross-presentation reinforcement, the vaccines elicit robust prophylactic efficacy for delaying B16-OVA and MC38 tumor occurrence, and show potent therapeutic efficacy for suppressing postoperative MC38 tumor recurrence and metachronous liver metastasis. Our study provides a versatile and powerful approach for fabricating personalized scaffold cancer vaccines.