Structure-corona-function engineering of micelles enables rapid hepatic bioactivation of clopidogrel for emergency antiplatelet therapy

Qinying Chen; Dali Chen; Zhihao Liu; Jipeng Wang; Xueyi Wang; Pingping Sun; Yun Qin; Zijin Tan; Yu Liu; Xiaochen Guo; Zhihui Hou; Yerong Xiong; Haichen Nie; Jiasheng Tu; Chunmeng Sun

doi:10.1016/j.jconrel.2026.114727

Structure-corona-function engineering of micelles enables rapid hepatic bioactivation of clopidogrel for emergency antiplatelet therapy

J Control Release. 2026 Feb 13:393:114727. doi: 10.1016/j.jconrel.2026.114727. Online ahead of print.

Authors

Qinying Chen¹, Dali Chen², Zhihao Liu², Jipeng Wang², Xueyi Wang², Pingping Sun², Yun Qin², Zijin Tan², Yu Liu², Xiaochen Guo², Zhihui Hou², Yerong Xiong³, Haichen Nie⁴, Jiasheng Tu⁵, Chunmeng Sun⁶

Affiliations

¹ State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China; Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China. Electronic address: qinying_chen@cpu.edu.cn.
² State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China; Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
³ School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
⁴ Department of Industrial and Molecular Pharmaceutics, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA. Electronic address: nie7@purdue.edu.
⁵ State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China; Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China. Electronic address: jiashengtu@cpu.edu.cn.
⁶ State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China; Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China. Electronic address: suncmpharm@cpu.edu.cn.

PMID: 41692042
DOI: 10.1016/j.jconrel.2026.114727

Abstract

Rapid platelet inhibition is essential for effective management during emergency percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS). However, the oral dosage form of clopidogrel (CLP) commonly used in clinical practice shows a delayed onset due to gastrointestinal absorption, first-pass metabolism, and the requirement for hepatic cytochrome P450 (CYP450)-mediated bioactivation, which limits its applications in urgent scenarios and complicating post-PCI bleeding management. To address these challenges, we developed an intravenous micellar formulation (CLP/PM) using FDA-approved mPEG-PLA copolymers to promote rapid hepatic exposure and metabolic activation. By tuning the PLA chain length, micellar core density and PEG conformation were modulated, thereby influencing protein corona (PC) formation and liver-affinity interactions. Proteomic profiling revealed that micelles with intermediate PLA length selectively recruited liver-affinity apolipoproteins (ApoM, ApoH, ApoA1, and ApoB), which are known ligands of LDLR and SR-BI, while minimizing adsorption of inflammatory and opsonization proteins. The optimized CLP/PM (3.9 k) exhibited a hepatotropic-like PC that was associated with hepatocyte-enriched uptake in primary liver cell analyses. In vivo biodistribution showed rapid liver-level signal, and pharmacokinetic studies supported enhanced CYP450-mediated activation, achieving a higher C_max of the active metabolite and shorter T_max of 22.5 ± 8.2 min. This translated into rapid-onset and potent antiplatelet efficacy, as reflected by prolonged bleeding time, diminished platelet reactivity, and reduced thrombus formation. Overall, these findings highlight a structure-corona-function framework for designing micelles that enhance hepatic prodrug bioactivation. By tuning PLA chain length, PC composition can be rationally modulated to optimize hepatic interaction and prodrug activation, providing a translational platform for rapid-onset and reversible platelet inhibition.

Keywords: Acute coronary syndrome; Antiplatelet; Clopidogrel; Liver delivery; Micelle; Protein corona.