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Herein, we devised an antitumor peptide\u2010based delivery platform in which both termini of a stapled p53 \u03b1\u2010helix are linked via a disulfide bond, thereby repurposing nonpolar residues originally involved in target protein (hDM2) binding as a hydrophobic block that drives co\u2010assembly with doxorubicin. Upon exposure to the reductive intracellular environment of cancer cells, cleavage of the disulfide bond induces \u03b1\u2010helix refolding, which triggers nanostructure disassembly and the coordinated release of both the antitumor peptide and doxorubicin. Furthermore, an RGD sequence was conjugated to the peptide terminus to confer cancer targeting functionality and enhance amphiphilicity owing to its high polarity. Within this platform, the resulting spherical nanocomplexes were well\u2010defined and exhibited pronounced protease resistance, efficient cellular internalization, and robust antitumor activity in vitro. In a xenograft colorectal cancer model, the nanocomplexes exhibited significantly enhanced antitumor efficacy with reduced off\u2010target toxicity compared to free doxorubicin, based on the complementary contribution of the peptide as both a therapeutic component and a delivery scaffold. This approach provides a versatile carrier\u2010free delivery platform based on its broad applicability to diverse small\u2010molecule drugs and peptide sequences.<\/jats:p>","DOI":"10.1002\/smll.75775","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T06:48:37Z","timestamp":1789195717000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Harnessing the Folding of Antitumor Peptides for Controlled Carrier\u2010Free Drug Delivery"],"prefix":"10.1002","author":[{"given":"Jae Yun","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Biological Sciences and Bioengineering Inha University  Incheon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moo Chang","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences and Bioengineering Inha University  Incheon Republic of 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