A pH-responsive polymeric nanovaccine with efficient endosomal escape and potent antitumor immunity for cancer treatment.

The efficacy of cancer vaccines is often limited by poor cytosolic antigen delivery. Here, we report a pH-responsive copolymer nanovaccine that remains inert under physiological conditions yet undergoes acid-triggered activation within endosomes. This activation induces membrane disruption and rapid antigen release, enhances endosomal escape, thereby enabling efficient cytosolic antigen delivery. These result in greatly enhanced antigen cross-presentation and dendritic cell maturation, which together drive strong activation and effector differentiation of antigen-specific CD8⁺ T cells. Through this approach the nanovaccine elicited strong cellular immunity and achieved marked tumor suppression with favorable biocompatibility across multiple murine tumor models. This work collectively provides a generalized, yet flexible strategy that overcomes the endosomal escape bottleneck and improves cytosolic antigen delivery for next-generation cancer vaccines. STATEMENT OF SIGNIFICANCE: (i) a mechanistically supported approach to improve endosomal escape for cytosolic antigen delivery; (ii) a polymer design framework that can be adapted to antigen delivery applications; (iii) in vivo evidence linking nanoscale material behavior to systemic antitumor immune responses.