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Here, we develop an affibody-drug conjugate nanoagent (ADCN) for the targeted codelivery of topoisomerase I inhibitor DX8591 and p53-MDM2 inhibitor PMI to upregulate p53 levels in cancer cells. The tripartite conjugate ZEGFR:1907-PMI-DX8591 self-assembled into nanoparticles with an average diameter of 74.4 nm, resulting in improved pharmacokinetic profiles and enhanced tumor-targeting ability. After efficient EGFR-mediated cellular uptake, the ZEGFR:1907-PMI-DX8591 ADCN released DX8591 and PMI intracellularly, leading to synergistic p53 activation by inducing p53 production and blocking its degradation. In EGFR-positive non-small cell lung tumor models, the ADCN showed excellent tumor accumulation and achieved 81.7% tumor growth inhibition, which was 1.5-fold and 1.2-fold higher than those of the ZEGFR:1907-PMI and ZEGFR:1907-DX8591 monotherapies, respectively. This affibody-based delivery system provides a promising strategy for synergistic cancer therapy.<\/jats:p>","DOI":"10.1021\/acs.molpharmaceut.6c00580","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T11:40:51Z","timestamp":1788435651000},"page":"4974-4987","source":"Crossref","is-referenced-by-count":0,"title":["A Self-Assembled Affibody-Drug Conjugate Nanoagent for EGFR-Targeted Synergistic Codelivery of Exatecan and an MDM2 Inhibitory Peptide"],"prefix":"10.1021","volume":"23","author":[{"given":"Mengqiao","family":"Zhao","sequence":"first","affiliation":[{"name":"Shanghai Jiao Tong University , , 800 Dongchuan Road , ,","place":["Shanghai, People\u2019s Republic of China, 200240"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9501-885X","authenticated-orcid":true,"given":"Wenhui","family":"Gao","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , 800 Dongchuan Road , ,","place":["Shanghai, People\u2019s Republic of China, 200240"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8371-0527","authenticated-orcid":true,"given":"Xuelin","family":"Xia","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , 800 Dongchuan Road , ,","place":["Shanghai, People\u2019s Republic of China, 200240"]},{"name":"Shanghai Jiao Tong University , , 800 Dongchuan Road , ,","place":["Shanghai, People\u2019s Republic of China, 200240"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8375-1616","authenticated-orcid":true,"given":"Xiao-Xia","family":"Xia","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , 800 Dongchuan Road , ,","place":["Shanghai, People\u2019s Republic of China, 200240"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0133-0605","authenticated-orcid":true,"given":"Zhi-Gang","family":"Qian","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , 800 Dongchuan Road , ,","place":["Shanghai, People\u2019s Republic of China, 200240"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"issue":"1","key":"2026100509321742500_cit1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1038\/s41573-024-01060-w","article-title":"DNA Damage Response Inhibitors in Cancer Therapy: Lessons from the Past, Current Status and Future Implications","volume":"24","author":"Drew","year":"2025","journal-title":"Nat. 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