Enhanced immunotherapy efficacy through molecularly imprinted nanoparticles co-targeting cluster of differentiation-73 and programmed death-ligand 1.

Abstract

Immune checkpoint blockade (ICB) therapy has emerged as an appealing cancer treatment strategy, yet its efficacy is frequently limited by insufficient T cell infiltration and an immunosuppressive tumor microenvironment (TME). To overcome these limitations, we developed a dual-checkpoint molecularly imprinted nanoblocker (dcMINB) for the simultaneous blockade of the cluster of differentiation-73 (CD73) and programmed death- ligand 1 (PD-L1). Precisely engineered via an advanced molecular imprinting technique, dcMINB functions as a bispecific artificial antibody that targets both CD73 and PD-L1 on tumor cells. Its surface is poly ethyleneglycol (PEG) modified to prolong systemic circulation. Upon intravenous administration in vivo, dcMINB preferentially accumulated in tumors and disrupted CD73-mediated adenosine (ADO) signaling while simultaneously blocking the PD-L1/programmed death receptor 1 (PD-1) axis. This dual inhibition markedly enhanced T cell infiltration and activation, resulting in robust antitumor efficacy with a tumor suppression rate of 81 %. This study not only provides a potent and translatable dual-checkpoint synergistic blockade strategy, but also paves the way for synergistic ICB-based treatment across various diseases. STATEMENT OF SIGNIFICANCE: Immune checkpoint blockade (ICB) has revolutionized oncology, yet its clinical benefits are often limited by inefficient drug delivery, a complex immunosuppressive tumor microenvironment (TME), and systemic toxicities. This work addresses these critical challenges by introducing a novel nanobiomaterial-a dual-checkpoint molecularly imprinted nanoblocker (dcMINB). Unlike conventional antibodies or simple nanoparticles, dcMINB is engineered using a sophisticated molecular imprinting technique to function as a synthetic, bispecific agent that simultaneously targets CD73 and PD-L1. This innovative approach demonstrates significant tumor-specific accumulation and dual blockade, effectively reversing immunosuppression by inhibiting both the adenosine pathway and the PD-1/PD-L1 axis. The result is a potent synergy that enhances T-cell infiltration and activation, leading to superior antitumor efficacy. Our work signifies a major step forward in biomaterials-based immunotherapy, offering a potent, translatable strategy with a unique mechanism of action that could broaden the therapeutic window for cancer treatment.