Engineering Dimeric Prodrug Nanoparticles Co-Delivering Paclitaxel and Immune Checkpoint Inhibitor to Boost Chemo-Immunotherapy

Abstract The combination of chemotherapy and immune checkpoint blockade-associated therapy shows great potential in combating malignant tumors. Nanodrug systems can effectively improve the delivery efficiency of chemotherapeutic and immune drugs. Herein, redox-responsive dimeric paclitaxel and bromodomain-containing protein 4 inhibitor prodrugs were synthesized and co-assembled into stable nanoparticles in the presence of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)2k]. After intravenous injection, the prepared nanodrugs can accumulate at tumors and respond to their redox microenvironment to release paclitaxel and an immune checkpoint inhibitor. The released paclitaxel can inhibit microtubule depolymerization to kill tumor cells, which also enhances immunogenic cell death, thereby promoting antitumor immune responses. In addition, this immune checkpoint inhibitor can effectively reduce the expression of programmed cell death ligand 1 to reverse the immune resistance, thus synergistically activating cytotoxicity T lymphocytes through remodeling the tumor immune microenvironment. As a result, these nanodrugs exhibit effective tumor suppression with alleviated systemic toxicity. This work provides valuable insight into constructing simple nanoplatforms to simultaneously deliver different therapeutics for effective tumor treatment.