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

Abstract

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.