A programmable platelet theranostic platform for adaptive multi-stage delivery and synergistic immunotherapy in atherosclerosis

Yi Li, Xueping Li, Ting Chen, Jian Li, Ji Qi () and Wen Li ()
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Yi Li: Chinese Academy of Medical Sciences and Peking Union Medical College
Xueping Li: Chinese Academy of Medical Sciences and Peking Union Medical College
Ting Chen: Chinese Academy of Medical Sciences and Peking Union Medical College
Jian Li: Chinese Academy of Medical Sciences and Peking Union Medical College
Ji Qi: Nankai University
Wen Li: Chinese Academy of Medical Sciences and Peking Union Medical College

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract Macrophages, along with the inflammatory and maladaptive immune responses they trigger, play crucial roles in the progression and rupture of atherosclerosis. We develop an adaptable platelet-protein platform tailored for the targeted delivery of both antioxidant nanocatalysts and TRAF6 inhibitor to advance synergistic therapy for atherosclerosis. The platform is constructed by assembling nanocatalyst- and TRAF6 inhibitor-loaded protein clusters with reactive oxygen species-cleavable linkers, then anchoring them onto the platelet surface for guided delivery to atherosclerotic plaques. Upon entering the reactive oxygen species-rich microenvironment, the platform disintegrates into ultra-small protein blocks, facilitating plaque penetration and selective macrophage internalization. The Mn-based nanocatalyst effectively scavenges various reactive oxygen species, while Mn ions concurrently enhance T1-weighted magnetic resonance imaging signals for diagnosis of atherosclerotic plaques. Meanwhile, the TRAF6 inhibitor blocks macrophage activation mediated by T lymphocytes. In a male mouse model of atherosclerosis, the versatile platform integrates cell-mediated natural targeting with adaptable size transformation for enhanced intraplaque penetration and unfavorable macrophage signaling reprogramming, offering opportunities for precise and multifaceted atherosclerosis therapy.

Date: 2025
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DOI: 10.1038/s41467-025-61789-9

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