Arterial　thrombosis　is　commonly　accompanied　by　poor　recanalization　and　high　recurrence,　typically　caused　by　a　fibrinolysis-resistant　microenvironment.　We　identify　elevated　levels　of　plasminogen　activator　inhibitor–1　(PAI-1)　and,　notably,　its　strong　correlation　with　inflammation　in　arterial　thrombosis.　To　address　this,　small　molecular　inhibitors　of　PAI-1　and　inflammation　are　used　as　bioregulators　to　restore　vascular　homeostasis.　We　design　a　carrier-free　supramolecular　system　based　on　the　bioregulators-tuned　self-assembly　of　a　near-infrared　thrombus　probe,　which　preferentially　forms　protein　corona　in　situ　to　enhance　plasma　stability.　Under　acidic　conditions　and　increased　shear　stress,　the　supramolecular　assemblies　disintegrate,　enabling　site-specific　cargo　release.　In　vivo,　the　probe　accumulates　22.8-fold　more　in　the　thrombotic　than　contralateral　artery.　Functionally,　this　nanomedicine　improves　outcomes　in　mice　with　carotid　artery　thrombosis　and　chronic　cerebral　ischemia.　Mechanistically,　it　down-regulates　NF-κB　signaling,　inhibits　NETosis　and　glycolysis,　and　up-regulates　cGMP-mediated　signaling,　thereby　alleviating　inflammation　and　promoting　fibrinolysis.　This　study　offers　an　innovative　codelivery　strategy　using　supramolecular　assemblies　to　advance　therapies　for　arterial　thrombosis.　Copyright　©　2025　The　Authors,　some　rights　reserved.