A carrier-free self-assembling nanovaccine comprising a STING agonist and antigenic peptides for controlled immune activation

The stimulator of interferon genes (STING) pathway plays a central role in antitumor immunity. However, the clinical application of cyclic dinucleotides (CDNs) as STING agonists is hampered by their poor stability and hydrophilicity. Critically, the systemic administration of free CDNs can lead to their entry into the bloodstream, causing systemic off-target inflammatory responses. However, the use of exogenous carriers can pose safety risks. Moreover, effective tumor therapy necessitates not only the activation of innate immunity but also robust antigen presentation to drive sufficient activation and expansion of T cells. To overcome these challenges, we developed a self-assembling nanovaccine by conjugating the STING agonist CDG^SF to the tumor antigen peptides (A02 and A24) via a cathepsin B-cleavable linker, leveraging the intrinsic self-assembling properties of the peptides. This conjugate spontaneously forms nanoparticles that are efficiently internalized by antigen-presenting cells (APCs), eliminating the need for additional delivery vehicles. Following cellular uptake, intracellular cathepsin B cleaves the linker to release CDG^SF and the antigens, thereby simultaneously activating the STING pathway and achieving highly efficient antigen presentation. This strategy mitigates the toxicity of free CDNs through controlled release, promotes precise immune activation, enhances antigen presentation and T-cell responses, and ultimately induces a potent, tumor-specific immune reaction.