Carrier-free Reduction-responsive Self-assembling Paclitaxel Dimer Nanoprodrug Synergising with Celastrol for Enhanced Chemoimmunotherapy

Chemotherapeutic paclitaxel (PTX) formulations are widely used in clinical cancer treatment; however, they are also associated with concomitant programmed death-ligand (PD-L1) upregulation and an immunosuppressive microenvironment. Herein, we rationally designed carrier-free, reduction-sensitive PTX dimer self-assembling nanoprodrugs (diPC NPs), composed of a glutathione (GSH)-responsive PTX dimer prodrug (diPTX) and the PD-L1 downregulator celastrol (Cel) for combinational chemoimmunotherapy. Following intravenous administration, the diPC NPs exhibited prolonged blood circulation and preferential tumour accumulation by exploiting the enhanced permeability and retention effect. Subsequently, the elevated GSH levels in tumour cells cleaved the disulfide bonds, triggering the rapid release of PTX and Cel. The released PTX elicited potent cytotoxic effects and induced immunogenic cell death (ICD), whereas the released Cel synergistically enhanced ICD and downregulated PD-L1 expression in tumour cells. Together, these effects resulted in remarkable antitumor efficacy with exhibited a favorable safety profile within the therapeutic window in both Lewis lung carcinoma cells and B16F10 tumour-bearing mice. Our findings highlight a promising strategy for highly efficient combination chemoimmunotherapy. KEY WORDS: Carrier-free; Reduction-responsive self-assembling; Paclitaxel dimer; Nanoprodrug; Celastrol; Chemoimmunotherapy.