Sequential supramolecular assembly of tannic acid and phenylboronic acid copolymers enabling enhanced cancer immunotherapy

Abstract

Cancer vaccines elicit responses of cytotoxic T lymphocytes (CTLs) and establish durable immune memory, offering promising cancer therapies. However, soluble tumor-associated antigens (TAAs) alone are rapidly cleared and poorly internalized by antigen-presenting cells (APCs), limiting cross-presentation and antitumor efficacy. Conventional nanoparticle-based delivery systems can prolong antigen retention but are often large (>100 nm), cationic, and cytotoxic, restricting their accumulation in lymph nodes (LNs) and impairing immune function. Here, to overcome these limitations, we report a sequentially self-assembled ternary complex composed of tannic acids (TA) and phenylboronic acid (PBA)-conjugated polymers for antigen delivery. Sequential coating of a protein antigen with TA and PBApolymers generated a core-shell structure with a diameter of ~20 nm and a neutral surface charge. Using ovalbumin (OVA) as a model protein antigen, we constructed the OVA-loaded ternary complex, and it exhibited significantly enhanced accumulation in draining LNs and uptake by APC. Within APCs, PBA-conjugated polymers dissociated from the complex in response to the acidic pH of a lateendosome/lysosome and induced the membrane destabilization through the hydrophobicity of deionized PBA and the cationic charge of residual lysine residues, enabling efficient endosomal escape and cross-presentation. Consequently, the ternary complex elicited potent CTL responses and inhibited the growth of OVA-expressing tumors with negligible adverse effects in mouse models. The ternary complex may be a promising antigen delivery platform.