Protein Nanovaccines Co-Delivering STING Agonists for Enhanced Dendritic Cell Activation and Antitumor Immunity.

Cancer nanovaccines offer great promise for eliciting antitumor immune responses, yet challenges persist in achieving efficient antigen delivery, robust immune activation, and formulation simplicity suitable for practical application. Here, we present a generalizable vaccine design strategy based on protein cross-linking combined with innate immune stimulation via the STING agonist MSA-2. This approach enables the construction of self-adjuvanted protein nanovaccines that unify tumor antigen stabilization, lymph node delivery, and immune activation within a single nanosystem. The representative formulation, M2-OVA-NP, efficiently activated the cGAS-STING signaling pathway in dendritic cells, promoted their maturation, and enhanced cytokine secretion and CD8+ T-cell priming. In vivo, the cancer nanovaccine accumulated effectively in draining lymph nodes, facilitated antigen presentation, and induced potent T-cell infiltration into the tumor microenvironment. These effects collectively resulted in significant tumor growth inhibition and improved survival in mice. This work demonstrates a simple and modular strategy for constructing protein-based self-adjuvanted nanovaccines that integrate antigen delivery with STING-mediated innate immune activation, providing a promising avenue for cancer immunotherapy.