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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,3,17]]},"abstract":"<jats:p>Inhibiting stimulator of interferon genes (STING) is critical for treating rheumatoid arthritis (RA), yet achieving precise suppression with high tissue specificity across protein variants remains challenging. Here, we engineer a multilevel, intelligent STING degrader\u2014charge-reversal proteolysis-targeting chimeras (CreTACs)\u2014that efficiently delivers to RA sites and degrades STING variants in humans, mice, and rats. Unlike traditional degraders with systemic toxicity, this charge reversal platform leverages pH-programmed charge inversion: Electroneutrality in circulation (pH 7.4) minimizes toxicity, while acidic-triggered protonation enables a 7.5-fold increase in arthritic joint accumulation (tissue level), pH-gated cellular internalization (80% uptake at pH 6.5 vs. 50% at pH 7.4; cellular level), and enhanced cytoplasmic STING (proton channel) affinity via charge interactions (protein level). In collagen-induced arthritis models, CreTACs outperformed methotrexate by suppressing synovitis and bone erosion without hematological toxicity. This multilevel charge reversal strategy establishes a blueprint for next-generation proteolysis drug-delivery systems or biomaterials, offering transformative potential for healthcare.<\/jats:p>","DOI":"10.1073\/pnas.2525897123","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T16:56:41Z","timestamp":1773334601000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":4,"title":["Charge-reversal proteolysis polymers enable tissue-specific STING degradation in rheumatoid arthritis"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-0390-9612","authenticated-orcid":false,"given":"Xu","family":"He","sequence":"first","affiliation":[{"name":"Institute of Clinical Pharmacology, Peking University First Hospital","place":["Beijing, People\u2019s Republic of China"]},{"name":"Department of Pharmacy, Peking University People\u2019s Hospital","place":["Beijing, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidong","family":"Gong","sequence":"additional","affiliation":[{"name":"Institute of Systems Biomedicine, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center","place":["Beijing, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology, Peking University First Hospital","place":["Beijing, People\u2019s Republic of China"]},{"name":"Department of Pharmacy, Peking University People\u2019s Hospital","place":["Beijing, People\u2019s Republic of China"]},{"name":"Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center","place":["Beijing, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaocong","family":"Pang","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology, Peking University First Hospital","place":["Beijing, People\u2019s Republic of China"]},{"name":"Department of Pharmacy, Peking University People\u2019s Hospital","place":["Beijing, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhui","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Peking University People\u2019s Hospital","place":["Beijing, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6244-3187","authenticated-orcid":false,"given":"Wei","family":"Wei","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences","place":["Beijing, People\u2019s Republic of China"]},{"name":"School of Chemical Engineering, University of Chinese Academy of Sciences","place":["Beijing, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimin","family":"Cui","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology, Peking University First Hospital","place":["Beijing, People\u2019s Republic of China"]},{"name":"Department of Pharmacy, Peking University People\u2019s Hospital","place":["Beijing, People\u2019s Republic of China"]},{"name":"Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center","place":["Beijing, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1834-2060","authenticated-orcid":false,"given":"Zhiqiang","family":"Lin","sequence":"additional","affiliation":[{"name":"Institute of Systems Biomedicine, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center","place":["Beijing, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,3,12]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(18)30255-4"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-00816-x"},{"key":"e_1_3_4_3_2","article-title":"The role of biologics in rheumatoid arthritis: A narrative review","volume":"15","author":"Patel J. P.","year":"2023","unstructured":"J. P. Patel , The role of biologics in rheumatoid arthritis: A narrative review. Cureus 15, e33293 (2023).","journal-title":"Cureus"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2022-223365"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(21)00220-4"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2019.105791"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2018-212988"},{"key":"e_1_3_4_8_2","first-page":"37","article-title":"Synergistically targeting synovium STING pathway for rheumatoid arthritis treatment","volume":"24","author":"Shen H.","year":"2022","unstructured":"H. Shen , Synergistically targeting synovium STING pathway for rheumatoid arthritis treatment. Bioact. Mater. 24, 37\u201353 (2022).","journal-title":"Bioact. 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