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Recent evidence has highlighted the importance of P2Y12R in microglial-neuron interactions, particularly in modulating mitochondrial quality control and mitigating oxidative stress. Here, we develop a dual-targeting nanoparticle system (P2Y-TK-Nano) to enhance P2Y12R expression in microglia and promote neuronal mitophagy, aiming to reduce mitochondrial reactive oxygen species (mtROS) and improve neuronal survival following SCI. The P2Y-TK-Nano system combines a ROS-responsive thioketal bond for injury-site targeting with an MG1 peptide to selectively target microglia. This design enables precise nanoparticle delivery to the ROS-enriched injury microenvironment, effectively restoring P2Y12R expression in microglia. Microglia treated with P2Y-TK-Nano exhibit elevated P2Y12R expression, leading to increased interaction with injured neurons, improved mitophagy, and reduced mtROS production. These combined effects significantly attenuate secondary damage and contribute to neuroprotection post-SCI. Our findings reveal a novel regulatory mechanism by which P2Y12R overexpression in microglia enhances neuronal mitophagy and mitigates oxidative stress after SCI. The dual-targeting P2Y-TK-Nano system offers a promising therapeutic approach to address microglial activation and mitochondrial dysfunction in the context of SCI.<\/jats:p>","DOI":"10.1038\/s41419-026-08596-2","type":"journal-article","created":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T14:44:06Z","timestamp":1776609846000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Dual-targeting nanoparticles enhance microglial P2Y12R expression to promote neuronal mitophagy for repairing spinal cord injury"],"prefix":"10.1038","volume":"17","author":[{"given":"Zhenming","family":"Tian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunheng","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiye","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubao","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Senyu","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mao","family":"Pang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4271-0310","authenticated-orcid":false,"given":"Xintao","family":"Shuai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0373-7393","authenticated-orcid":false,"given":"Limin","family":"Rong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,19]]},"reference":[{"key":"8596_CR1","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1038\/nature12808","volume":"505","author":"TL Roth","year":"2014","unstructured":"Roth TL, Nayak D, Atanasijevic T, Koretsky AP, Latour LL, McGavern DB. 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