Carrier-Free Small-Molecule Drug Nanoassembly Elicits Chemoimmunotherapy via Co-inhibition of PD-L1/mTOR.

The growth and progression of tumor are promoted by multiple cytokines, which are overactivated in the tumor microenvironment. Co-inhibiting the activities of these cytokines is expected to realize the enhanced therapeutic outcome of cancer. However, reasonable combinational strategies are still limited. Herein, a nanoassembly structure that was totally formed by the assembly of small-molecule inhibitors is constructed for the co-inhibition of mTOR and PD-L1. Together with the NIR dye IR783, Rapa and (+)-JQ1 assemble to form a stable nanoassembly structure with controllable particle size. The JQ1/Rapa-IR783 nanoassembly efficiently downregulates the PD-L1 level as well as the level of PKM2. The combination of Rapa and (+)-JQ1 enhances the apoptosis of cancer cells compared with that following treatment with Rapa or (+)-JQ1 alone. assays conducted to evaluate tumor growth inhibition mediated by the nanoassemblies revealed that the simultaneous delivery of Rapa and (+)-JQ1 not only inhibited the growth of primary tumors but also alleviated pulmonary metastasis by reinvigorating the immune system as the result of the downregulation of both mTOR and PD-L1. It demonstrates that the nanoassembly structure is a promising candidate for the codelivery of immunomodulator for enhanced cancer immunotherapy.