Precisely deliver toll-like receptor agonists using a dual-responsive nanovaccine for effective cancer immunotherapy

Cancer vaccines have demonstrated their potential in cancer immunotherapy. However, various agonists in free form are easily to be eliminated in vivo and may cause systemic adverse effects. It remains a challenge to effectively target and release agonists at their receptor locations and prevent undesirable leakage. Herein, we present a dual-responsive nanovaccine (DRNV) for targeted delivery of toll-like receptor (TLR) agonists. DRNV was formed by self-assembly of antigen and degradable amphiphilic polymer, polyethylene glycol modified poly (lipoic acid) (PTA). Imidazoquinoline (IMDQ), a classical TLR7/8 agonist, was covalently conjugated to PTA with an enzyme-responsive linker. With this design, DRNV can avoid rapid elimination and potential toxicity due to systemic diffusion. Furthermore, the PTA core would be quickly degraded in response to intracellular glutathione, leading to the disintegration of DRNV and promoting enzyme-responsive release of IMDQ, ultimately stimulating TLR7/8 receptors on the inner membrane of endosomes. Systemic animal experiments demonstrated that DRNV effectively inhibits tumor growth and triggers protective antitumor immune responses to against tumor rechallenge and metastasis. Overall, this work demonstrates a feasible nanoplatform for the precise delivery of TLR agonists and tumor antigens, providing insights into the design of advanced nanovaccine for effective and safe cancer immunotherapy.