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Here, we introduced an unconventional solution: Imparting autonomous motility to nPROs to transform them from passive carriers into active protein\u2010seeking degraders. We engineered nano\u2010motoring PROTACs (nMPROs) through asymmetric modification of gold nanoparticles, displaying POI ligands and E3 recruiters on one hemisphere while anchoring catalase on the opposite hemisphere. Within the H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    \u2010rich tumor cell microenvironment, catalase\u2010generated oxygen fueled directional propulsion, enabling nMPROs to actively navigate the intracellular space rather than relying on random diffusion. This propulsion fundamentally enhanced intracellular target\u2010search efficiency: nMPROs function as \u201cnanoscopic protein\u2010sweeping robots,\u201d autonomously interrogating a larger intracellular landscape and capturing more sparsely distributed target proteins. As a result, nMPROs achieved a threefold increase in ER\u03b1 degradation potency relative to static nPROs and enabled modular, ligand exchange\u2013based degradation of PD\u2010L1, demonstrating platform generality. Overall, this work establishes a new mechanistic paradigm for enhancing targeted protein degradation of nPROs and lays the foundation for generalizable next\u2010generation PROTAC nanoplatforms.\n                  <\/jats:p>","DOI":"10.1002\/adma.73991","type":"journal-article","created":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T15:41:04Z","timestamp":1783179664000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Autonomously Motile Nano\u2010PROTACs Act as Protein\u2010Sweeping Robots to Enhance Targeted Protein Degradation"],"prefix":"10.1002","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6166-9881","authenticated-orcid":false,"given":"Xiang","family":"Lu","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences Zhengzhou University  Zhengzhou China"},{"name":"Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment  Zhengzhou China"},{"name":"Pingyuan Laboratory, State Key Laboratory of Antiviral Drugs  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Furui","family":"Qiu","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijie","family":"Liang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomin","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Xue","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianghao","family":"Wang","sequence":"additional","affiliation":[{"name":"Hangzhou Matridx Biotechnology Co. Ltd.  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1531-7265","authenticated-orcid":false,"given":"Jinjin","family":"Shi","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Zhengzhou University  Zhengzhou China"},{"name":"Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment  Zhengzhou China"},{"name":"Pingyuan Laboratory, State Key Laboratory of Antiviral Drugs  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7620-3609","authenticated-orcid":false,"given":"Hongling","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Zhengzhou University  Zhengzhou China"},{"name":"Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment  Zhengzhou China"},{"name":"Pingyuan Laboratory, State Key Laboratory of Antiviral Drugs  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binghua","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Zhengzhou University  Zhengzhou China"},{"name":"Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment  Zhengzhou China"},{"name":"Pingyuan Laboratory, State Key Laboratory of Antiviral Drugs  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,4]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010024\u201001983\u20101"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571\u2010023\u201000736\u20103"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010025\u201002444\u2010z"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010025\u201061272\u20105"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2CS00193D"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2CS00220E"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2CS00200K"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00371-6"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1858"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2016.211"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201023194\u2010w"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568\u2010021\u201000365\u2010x"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202218128"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/d41573\u2010024\u201000187\u20100"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c06402"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010022\u201000999\u20109"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2023.108371"},{"key":"e_1_2_8_19_1","article-title":"Tumor\u2010Activated Carrier\u2010Free Prodrug Nanoparticles for Targeted Cancer Immunotherapy: Preclinical Evidence for Safe and Effective Drug Delivery","volume":"183","author":"Shim M. 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