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Due to hydrophilic polyanionic backbone, their efficacy was fundamentally constrained by inefficient cellular internalization. Here, we engineered a self\u2010assembled aptamer\u2010derived PROTAC (SADP) featuring a dual\u2010hydrophobic module composed of an alkyl linker and a separate fatty acid. The alkyl linker could modulate the spatial arrangement between the aptamer and E3 ligand while also synergize with the fatty acid to drive formation of SADP nanomicelles for cellular internalization enhancement. As a proof of concept, SADP (Apt\u2010F\u201010\u2010V) was screened and achieved approximately five\u2010fold higher internalization efficiency than conventional aptamer\u2010derived PROTAC, resulting in potent intracellular sclerostin degradation (DC\n                    <jats:sub>50<\/jats:sub>\n                    = 76.8\u00a0nM, Dmax = 82%) in triple\u2010negative breast cancer (TNBC) cells. Mechanistically, Apt\u2010F\u201010\u2010V could be internalized via clathrin\u2010mediated endocytosis, followed by lysosomal disassembly and escape into the cytoplasm. The liberated monomers could induce a sclerostin\/PROTAC\/VHL ligase ternary complex for intracellular sclerostin degradation. Importantly, Apt\u2010F\u201010\u2010V demonstrated tumor accumulation and robust tumor suppression in both TNBC cell\u2010derived and patient\u2010derived xenograft models. This study presents that cooperative micellization of aptamer\u2010derived PROTAC could overcome the cellular internalization barrier, enabling potent intracellular sclerostin degradation and TNBC therapy.\n                  <\/jats:p>","DOI":"10.1002\/adhm.71723","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T04:45:58Z","timestamp":1789361158000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Self\u2010Assembled Aptamer\u2010Derived PROTAC Enables Efficient Cellular Internalization for Intracellular Sclerostin Degradation and Triple\u2010Negative Breast Cancer Therapy"],"prefix":"10.1002","volume":"15","author":[{"given":"Hang","family":"Luo","sequence":"first","affiliation":[{"name":"School of Chinese Medicine The Chinese University of Hong Kong  Hong Kong 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