A Polyprodrug Nanomedicine for Optimized Cancer Chemoimmunotherapy by Precise and Ratiometric Delivery of Therapeutic Combinations

Chemoimmunotherapy represents a promising therapeutic modality in clinical tumor treatment. For this strategy, multiple drugs need to be delivered into tumors in an optimal ratio to achieve the desired drug synergism and therapeutic effects. However, the barriers in conventional drug combination screening in vitro and precise/ratiometric drug delivery in vivo remain a major concern in the clinical translation of chemoimmunotherapy. Herein, a polyprodrug nanoplatform is constructed to enable ratiometric loading and synchronized release of chemotherapeutic camptothecin (CPT) and immunotherapeutic NLG919 in the GSH-abundant tumor tissues. Instead of relying on tumor cell lines and organoids in vitro for drug screening, the optimal CPT/NLG919 ratios in polyprodrug nanomedicines are systematically evaluated based on their in vivo antitumor and immune activation performance. Consequently, the polyprodrug nanomedicine codelivering CPT and NLG919 at a ratio of 1:5 exhibited the most pronounced suppression on primary tumors, distant tumors, and metastatic tumors and elicited the strongest antitumor immune responses. This study not only provides a reliable platform for optimized antitumor efficacy in chemoimmunotherapy but also offers in vivo drug screening principles for combination nanomedicines.