Prospects and challenges of traditional Chinese medicine supramolecular nano-drug delivery systems in the treatment of cerebral ischemia.

Ischemic stroke is a leading cause of permanent disability and death worldwide. Effective neuroprotective therapy is hindered by two major obstacles: the blood-brain barrier and the complex pathological cascades triggered by reperfusion injury. Supramolecular traditional Chinese medicine (STCM) refers to nano-aggregates that spontaneously form during herbal decoction. These natural assemblies offer several advantages for brain-targeted delivery, including biocompatibility, structural adaptability, multi-component synergy, and responsiveness to the lesion microenvironment. This review begins by examining the pathological microenvironment of the ischemic penumbra. In this region, acidosis, elevated reactive oxygen species, and upregulated matrix metalloproteinases act as endogenous stimuli triggering the disassembly of STCM nanostructures and the release of drugs at the site of injury. We then trace the development of TCM-based nanocarriers and describe four BBB-crossing mechanisms that are unique to STCM. These include glycan-mediated self-targeting through multivalent surface interactions, enhanced permeation through co-assembly with aromatic resuscitation herbs, reversible disassembly of non-covalent networks in response to pathological signals, and functional synergy among paired herbal components. We also summarize preclinical evidence for the use of STCM in ischemic stroke therapy, synthesizing data from representative active ingredients and herb pairs. Finally, we evaluate translational bottlenecks and propose strategic research directions. This work establishes a unified theoretical and methodological foundation for designing STCM-based precision brain-targeted therapeutics against cerebral ischemia.