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Although dermal papilla cells (DPCs) exhibit intrinsic scar-inhibitory potential, their therapeutic utility is constrained by rapid replicative senescence and poor scalability in traditional monolayer cultures, necessitating innovative strategies to enhance cellular functionality and manufacturing feasibility.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A self-feeder layer 3D (SFL-3D) platform was established to reprogram primary human DPCs into rejuvenated three-dimensional DPC (tdDPC) spheroids via autocrine\u2013paracrine signalling activation. tdDPC-derived extracellular vesicles (tdDPC-EVs) were isolated from culture supernatants by differential centrifugation. The antifibrotic effects of tdDPC-EVs were systematically evaluated using human scar fibroblasts through scratch wound healing assays, CCK-8 proliferation assays, and fibrotic marker analysis [Western blotting and immunofluorescence staining for \u03b1-smooth muscle actin (\u03b1-SMA) and collagen I]. Bioinformatics was used to predict key pathways involved in hypertrophic scar (HS) pathogenesis, whereas gain\/loss-of-function studies investigated the miR-26a-5p\/CCNE2 regulatory axis. Therapeutic validation was performed in a rabbit ear hypertrophic scar model with histopathological and molecular profiling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Compared with conventional 3D cultures, the SFL-3D system demonstrated superior proliferative support, enabling stable tdDPC expansion beyond 10 passages while maintaining high viability and enhanced EV biogenesis. miR-26a-5p-enriched tdDPC-EVs attenuated fibrosis through two mechanisms: (1) silencing CCNE2 to block PI3K\/AKT-driven collagen overproduction and (2) suppressing \u03b1-SMA\u2009+\u2009myofibroblast differentiation. In the rabbit ear HS model, tdDPC-EV administration reduced the scar elevation index and restored the collagen I\/III ratio to near-physiological levels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study positions tdDPC-EVs as a scalable acellular therapy that overcomes the replicative senescence and manufacturing limitations of cellular approaches. The antiscarring efficacy of these EVs, which is mediated by the miR-26a-5p\/CCNE2\/PI3K\/AKT axis, highlights their clinical potential as precision-targeted strategies for hypertrophic scar management. The SFL-3D platform further provides a translatable framework for EV-based regenerative therapeutics.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/burnst\/tkaf048","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T11:17:24Z","timestamp":1753096644000},"source":"Crossref","is-referenced-by-count":2,"title":["Self-organizing three-dimensional dermal papilla cell spheroids yield therapeutic extracellular vesicles that target hypertrophic scar regression via the miR-26a-5p\/CCNE2 axis"],"prefix":"10.1093","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5845-1785","authenticated-orcid":false,"given":"Yunwei","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University , 127 West Changle Road, Xi\u2019an, Shaanxi 710032 ,","place":["China"]},{"name":"Department of Burn Plastic and Wound Repair Surgery, Lanzhou University Second 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