Surface‐Anchored Ticagrelor Gelatin Nanoparticles‐Platelets System for Enhanced Anti‐PD‐L1 Therapy Response and Boosted Chemotherapeutic Efficacy of Nanomedicines

The tumor microenvironment is characterized by immunosuppression and compromised intratumoral perfusion, which impairs the effectiveness of immune checkpoint inhibitors and nanomedicines. A significant challenge is the role of activated platelets, as they increase transfer-mediated PD-L1 expression from tumor cells and maintain the integrity of tumor vasculature. These platelets support tumor growth by stabilizing the vasculature and enabling immune evasion, as well as shielding tumor cells from immune detection. To address these platelet-mediated negative antitumor effects, we have developed bioengineered platelets (PTNPs) with surface-anchored ticagrelor-loaded gelatin nanoparticles. This study utilizes the natural tendency of platelets to localize their activated counterparts into tumors. Upon binding to tumor-associated activated platelets, the PTNPs release ticagrelor in response to the secreted matrix metalloproteinases by activated platelet, inhibiting further platelet activation. This reduction in platelet activation lessens platelet-facilitated immunosuppression and diminishes the transferred-PD-L1 expression from cancer cells to platelets, thus enhancing the immune response of anti-PD-L1 therapy. Additionally, this strategy weakens the activated platelets' contribution to tumor vascular integrity, improving the extravasation and chemotherapeutic efficacy of nanomedicines. Our findings highlight the crucial role of platelet activation in tumor biology and introduce PTNPs as an effective approach to disrupt tumor-supporting platelet activities and enhance anticancer treatments efficacy.