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The deep coverage analysis of in situ protein conformations and interactions in the mitochondria of living cells remains challenging, due to the limited delivery and release efficiency of cross\u2010linkers. Herein, we developed a mitochondria\u2010targeted and dual\u2010responsive nanogel system that integrated reactive oxygen species (ROS)\u2010cleavable thioketal bonds and thermosensitive phase\u2010transition elements for mitochondria\u2010specific delivery and fast release of cross\u2010linkers. Compared to previous polymeric micelle systems, the nanogel showed expansive compatibility with hydrophilic cross\u2010linkers, whose efficient release under the elevated ROS and temperature of mitochondria contributed to high cross\u2010linking coverage. Using this nanogel system, 3927 intra\u2010links and 904 inter\u2010links across 783 mitochondrial proteins were\u00a0identified, representing a 2.3\u2010fold increase in the number of cross\u2010links compared to the previously developed ROS\u2010responsive polymeric micelle system. These data revealed the possible existence of ATP synthasome and flexible or membrane\u2010associated conformations inaccessible to crystallography. This work establishes an efficient strategy for in situ conformation and interaction analysis of mitochondrial proteins in the native environment, which is helpful for understanding the mitochondrial protein function.<\/jats:p>","DOI":"10.1002\/smll.202512157","type":"journal-article","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T11:03:30Z","timestamp":1767870210000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Dual\u2010Responsive Nanogel for Mitochondria\u2010Targeted Delivery and Release of Cross\u2010Linkers to Decipher In Vivo Protein Conformations and Interactions"],"prefix":"10.1002","volume":"22","author":[{"given":"Wen","family":"Zhou","sequence":"first","affiliation":[{"name":"State Key Laboratory of Medical Proteomics National Chromatographic R. &amp; A. 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