Advancements in Natural Product-Based Ischemic Stroke Treatment: Mechanisms, Key Compounds, and Drug Delivery Systems

Ischemic stroke (IS) remains the leading global cause of permanent neurological disability and mortality. Narrow therapeutic time windows and elevated hemorrhagic transformation risks restrict conventional clinical interventions, including intravenous thrombolysis and mechanical thrombectomy. Single-target neuroprotective agents fail to sustain long-term neurological functional recovery, resulting in unsatisfactory clinical outcomes. Natural products (NPs) derived from traditional Chinese medicine exert protective effects against cerebral ischemia via multiple pathways. However, their poor blood-brain barrier (BBB) permeability, low aqueous solubility, and inadequate in vivo bioavailability greatly hinder clinical translational application. This review systematically summarizes the pathological mechanisms of natural monomers for the treatment of ischemic stroke and four types of brain-targeted nanocarriers over the past decade. We reconstructed the pathological cascades of cerebral ischemia across the acute, subacute, and chronic repair phases, and critically discussed the inherent limitations of the middle cerebral artery occlusion (MCAO) model and existing monomer-based preclinical studies. This work provides systematic structure-activity relationship evidence and insights into nano-delivery strategies for the development of natural product-based anti-stroke therapeutics. We also propose future research directions, such as staged, sequential administration, precise multi-omics intervention, and standardized nanoformulation development, to accelerate the clinical translation of bioactive ingredients derived from traditional Chinese medicine.