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One potential therapeutic agent, hypericin (HYP), is identified as an effective natural antidepressant. However, its poor water solubility, low bioavailability, and limited ability to penetrate the brain parenchyma have hindered its clinical application. To address these shortcomings and enhance the therapeutic efficacy of HYP, it is loaded onto black phosphorus nanosheets (BP) modified with the neural cell\u2010targeting peptide RVG29 to synthesize a nanoplatform named BP\u2010RVG29@HYP (BRH). This platform served as a nanocarrier for HYP and integrated the advantages of BP with advanced delivery methods and precise targeting strategies. Under the influence of 808\u00a0nm near\u2010infrared irradiation (NIR), BRH effectively traversed an in vitro BBB model. In vivo experiments validated these findings, demonstrating that treatment with BRH significantly alleviated depressive\u2010like behaviors and oxidative stress in mice. Importantly, BRH exhibited an excellent safety profile, causing minimal adverse effects, which highlighted its potential as a promising therapeutic agent. In brief, this novel nanocarrier holds great promise in the development of antidepressant drugs and can create new avenues for the treatment of depression.<\/jats:p>","DOI":"10.1002\/smll.202310608","type":"journal-article","created":{"date-parts":[[2024,3,10]],"date-time":"2024-03-10T15:56:28Z","timestamp":1710086188000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Brain\u2010Targeted Black Phosphorus\u2010Based Nanotherapeutic Platform for Enhanced Hypericin Delivery in Depression"],"prefix":"10.1002","volume":"20","author":[{"given":"Hanxu","family":"Tan","sequence":"first","affiliation":[{"name":"School of Fundamental Medical Science Guangzhou University of Chinese Medicine  Guangzhou 510006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerun","family":"Cao","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Translational Cancer Research of 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