Rationally Engineered Bispecific Nanoimmunoblocker Restores Anticancer Immunity via Dual Immune Checkpoint Blockade.

Abstract

Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment. However, the outcomes of mainstay antibody inhibitors against solid tumors remain poor, facing tremendous challenges including manufacturing complexities, serious toxicities, and crosstalk among multiple checkpoints. Herein, we present a bispecific molecularly imprinted nanoimmunoblocker (bsMINIB) designed to boost potent antitumor immunity via synchronously blocking innate and adaptive immune checkpoints. Two epitopes for PD-L1 and SIRPα are selected as templates through structural analysis, and thereafter, bsMINIB capable of bridging tumor cells and macrophages is rationally engineered via an advanced imprinting approach. The bsMINIB exhibits high affinity and specificity toward PD-L1 on solid tumor cells and SIRPα on macrophages, allowing effective disruption of both PD-L1/PD-1 and CD47/SIRPα signaling. These signal disruptions restore macrophage-mediated tumor phagocytosis, promote tumor-associated antigen presentation, and reinvigorate T cell-mediated tumor killing. Using refractory triple-negative breast cancer as a solid tumor model, the bsMINIB demonstrates extended retention at the tumor site, amplified infiltration of active T cells, and reactivated antitumor macrophages, thereby effectively inhibiting tumor growth. This biomimetic nanoimmunoblocker not only presents an effective multipronged ICB therapeutic against solid tumors but also showcases a compelling paradigm for the rational engineering of bispecific nanoplatforms for synergistic immunotherapy through molecular imprinting.