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Hydrogel delivery of apoptotic neutrophils modulates macrophage angiogenic and inflammatory responses during wound healing

ABSTRACT: Effective wound healing requires coordinated angiogenesis and immune resolution. Biomaterial systems support tissue regeneration but typically lack intrinsic immunomodulatory signals needed to actively direct immune resolution and angiogenesis. In this study, localized delivery of apoptotic neutrophils (AN) encapsulated within Gelatin methacryloyl (GelMA) hydrogels was evaluated for its ability to enhance angiogenic responses and modulate inflammatory activity in vivo. In a murine splinted full-thickness skin wound model, AN-loaded GelMA significantly increased vessel length and CD31⁺ vascular area at 14 days post-wounding, while also enhancing cellular infiltration and hydrogel retention. Single-cell RNA sequencing (scRNA-seq) at day 5 post-wounding revealed that AN incorporation reshapes the early wound landscape, enriching macrophage states associated with tissue remodeling and increasing expression of efferocytosis-associated genes across myeloid populations while reducing inflammatory gene expression and altering chemokine expression. Intercellular communication analysis demonstrateds that AN-loaded GelMA shifts endothelial-myeloid signaling away from pro-inflammatory interactions toward pro-resolving signaling programs and enhances vascular crosstalk. In vitro assays confirmed modulation of macrophage paracrine activity, with reduced pro-inflammatory cytokine production, enhanced anti-inflammatory responses, and differential regulation of angiogenesis-associated gene expression. HUVEC vessel-like tube formation assay demonstrated that conditioned media from both GelMA- and AN-treated macrophages support endothelial network formation in vitro. Together, these findings demonstrate that combining GelMA hydrogel with AN-derived cues establishes a pro-resolving environment that reprograms macrophage states and coordinates vascular remodeling, highlighting a promising immunomodulatory biomaterial strategy for wound healing applications.

ORGANISM(S): Mus musculus

PROVIDER: GSE336668 | GEO | 2026/07/02

REPOSITORIES: GEO

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Project description:Diabetic wounds require continuous and coordinated modulation of the microenvironment concurrent with tissue regeneration, yet this remains a significant challenge. As a proof of concept, we herein propose to use dimeric copper peptide for diabetic wound treatment. The dimeric copper peptide (D-CuP) was first synthesized and then incorporated into a reactive oxygen species (ROS)-responsive hydrogel matrix to improve therapeutic compliance, culminating in the formulation of G/D-CuP. Compared to monomer copper peptide (CuP), a wound healing agent, D-CuP exhibits multivalency, enhanced biologic stability against proteases and the broad biological activities, such as anti-inflammatory and antioxidative properties, while promoting angiogenesis and fibroblast proliferation and migration. Meanwhile, the hydrogel matrix, exhibiting excellent ROS-scavenging capabilities, has been engineered to an intelligent drug reservoir for wound-responsive release of D-CuP at the wound site while simultaneously attenuating inflammatory responses. Ultimately, the G/D-CuP group demonstrated superior therapeutic efficacy, achieving in 97.2% closure of infected wounds.In this study, we present a proof-of-concept study to optimize the treatment of diabetic wounds. This method integrates a dimeric copper peptide hydrogel (G/D-CuP) to address several critical factors: i) The design and synthesis of the dimeric copper peptide (D-CuP) feature a broad range of targets and enhanced biological activities, such as anti-inflammatory and antioxidative properties, while promoting angiogenesis and fibroblast proliferation and migration; ii) Utilizing the steric hindrance conferred by dimerization reduces protease access to the active site and significantly improving stability against proteases; iii) A ROS-responsive hydrogel matrix has been synthesized, exhibiting superior ROS-scavenging capabilities, functioning as an intelligent drug reservoir that enables the controlled release of D-CuP at the wound interface while simultaneously attenuating inflammatory responses in the microenvironment; iv) G/D-CuP possesses outstanding deformability and spreadability, allowing it to adapt to any wound shape; v) The synthesis and preparation process of G/D-CuP are straightforward and cost-effective, making it highly promising for clinical translation. This multifunctional treatment platform is anticipated to accommodate the complex and dynamic biological processes involved in diabetic wound healing, thereby significantly improving the overall efficacy of wound healing treatments.

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Hydrogel delivery of apoptotic neutrophils modulates macrophage angiogenic and inflammatory responses during wound healing

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