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Studies revealed that tPA has been observed to have both neurotrophic and neurotoxic effects. It is still unclear how these opposite functions are modulated by tPA but the degree of maturity and\/or the type of neurons, structure of the tPA, origin, and amount have been suggested as effective factors. The sole FDA-approved thrombolytic medication for acute ischemic stroke is tPA, yet worries about its limits still exist. Due to tPA\u2019s limitations, conventional thrombolytic therapy for ischemic stroke by tPA occasionally results in problems or insufficient therapeutic effects. The results indicated that if tPA was given within the time latency window of up to 3\u00a0h it could significantly increase the propensity for cell survival. tPA\u2019s ability to influence different cellular pathways suggest that targeting the desired ones could increase the therapeutic window of tPA in stroke recovery. To provide even better neuroprotection following an acute cerebral infarct, future therapeutics could focus on preventing the neurotoxic damage caused by tPA. In this review, we will discuss the current overview abroad tPA and the current knowledge concerning the natural history of tPA and aim to identify the relevant cellular signaling mechanisms underlying the tPA-mediated effects in-vitro. We also reviewed the present applications of several nanocarriers intended for the administration of tPA in ischemic strokes while also reviewing the biology, thrombolytic mechanism, and pleiotropic roles of tPA in the brain. We\u2019ve also discussed the difficulties and the probable future of tPA-based Nano thrombolysis in stroke treatments.<\/jats:p>","DOI":"10.1007\/s12031-025-02443-3","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T01:51:45Z","timestamp":1763344305000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Tissue Plasminogen Activator as an Approved Strategy for Ischemic Stroke: A Review of tPA\u2019s Structure, Mechanism of Action and the Novel Targeting Methods"],"prefix":"10.1007","volume":"75","author":[{"given":"Kimia","family":"Didehvar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehdi","family":"Haghshenas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reyhaneh","family":"Yarmohammadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bardia","family":"Hajikarimloo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roya","family":"Ghafoury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,17]]},"reference":[{"issue":"1","key":"2443_CR1","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/nrn1824","volume":"7","author":"NJ Abbott","year":"2006","unstructured":"Abbott NJ, R\u00f6nnb\u00e4ck L, Hansson E (2006) Astrocyte\u2013endothelial interactions at the blood\u2013brain barrier. 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