Nanodisc-Forming Polymers as TLR7/8 Agonist-Conjugated Immunotherapy Agents

Amphiphilic polymers can solubilize membrane proteins in what is coined native lipid nanodiscs, although their potential as drug delivery platforms is mostly unexplored. Herein, we covalently attached a Toll-like receptor 7/8 agonist to poly(acrylic acid-co-styrene) to generate a multimodal cancer immunotherapy platform (AASTY-TLR7/8ag.) that acts as a loco-regional Toll-like receptor 7/8 agonist depot and as a nanodisc-driven in situ immunization platform. We show that AASTY-TLR7/8ag. therapy translates into tumor growth inhibition in CT26 and other murine cancer models, with the induction of immune memory, synergy with anti-PD-1, and limited on-target/off-tumor toxicity. By formulating nanodiscs from cancer cell membranes in vitro, we also observed that subcutaneous injection in mice leads to rapid distribution in lymph nodes and immune activation of dendritic cells, highlighting the broader potential of AASTY-TLR7/8ag. as a tool for immunization.