Endogenous stimuli-responsive separating microneedles to inhibit hypertrophic scar through remodeling the pathological microenvironment

Zhuo-Ran Yang, Huinan Suo, Jing-Wen Fan, Niannian Lv, Kehan Du, Teng Ma, Huimin Qin, Yan Li, Liu Yang, Nuoya Zhou, Hao Jiang (), Juan Tao () and Jintao Zhu ()
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Zhuo-Ran Yang: Huazhong University of Science and Technology (HUST)
Huinan Suo: Tongji Medical College, HUST
Jing-Wen Fan: The Forth Military Medical University (FMMU)
Niannian Lv: Huazhong University of Science and Technology (HUST)
Kehan Du: Huazhong University of Science and Technology (HUST)
Teng Ma: Huazhong University of Science and Technology (HUST)
Huimin Qin: Huazhong University of Science and Technology (HUST)
Yan Li: Tongji Medical College, HUST
Liu Yang: Tongji Medical College, HUST
Nuoya Zhou: Tongji Medical College, HUST
Hao Jiang: Huazhong University of Science and Technology (HUST)
Juan Tao: Tongji Medical College, HUST
Jintao Zhu: Huazhong University of Science and Technology (HUST)

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Hypertrophic scar (HS) considerably affects the appearance and causes tissue dysfunction in patients. The low bioavailability of 5-fluorouracil poses a challenge for HS treatment. Here we show a separating microneedle (MN) consisting of photo-crosslinked GelMA and 5-FuA-Pep-MA prodrug in response to high reactive oxygen species (ROS) levels and overexpression of matrix metalloproteinases (MMPs) in the HS pathological microenvironment. In vivo experiments in female mice demonstrate that the retention of MN tips in the tissue provides a slowly sustained drug release manner. Importantly, drug-loaded MNs could remodel the pathological microenvironment of female rabbit ear HS tissues by ROS scavenging and MMPs consumption. Bulk and single cell RNA sequencing analyses confirm that drug-loaded MNs could reverse skin fibrosis through down-regulation of BCL-2-associated death promoter (BAD), insulin-like growth factor 1 receptor (IGF1R) pathways, simultaneously regulate inflammatory response and keratinocyte differentiation via up-regulation of toll-like receptors (TOLL), interleukin-1 receptor (IL1R) and keratinocyte pathways, and promote the interactions between fibroblasts and keratinocytes via ligand-receptor pair of proteoglycans 2 (HSPG2)-dystroglycan 1(DAG1). This study reveals the potential therapeutic mechanism of drug-loaded MNs in HS treatment and presents a broad prospect for clinical application.

Date: 2024
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DOI: 10.1038/s41467-024-46328-2

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