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The dynamic balance between hypoxia and oxidative stress constitutes the oxygen-related microenvironment in injured tissues. Due to variability, oxygen homeostasis is usually not a therapeutic target for injured tissues. It is found that when administered intravenously, mesenchymal stem cells (MSCs) and in vitro induced apoptotic vesicles (ApoVs) exhibit similar apoptotic markers in the wound microenvironment where hypoxia and oxidative stress co-existed, but MSCs exhibited better effects in promoting angiogenesis and wound healing. The derivation pathway of ApoVs by inducing hypoxia or oxidative stress in MSCs to simulate oxygen homeostasis in injured tissues is improved. Two types of oxygen-related environmental stressed ApoVs are identified that directly target endothelial cells (ECs) for the accurate regulation of vascularization. Compared to normoxic and hypoxic ones, oxidatively stressed ApoVs (Oxi-ApoVs) showed the strongest tube formation capacity. Different oxygen-stressed ApoVs deliver similar miRNAs, which leads to the broad upregulation of EC phosphokinase activity. Finally, local delivery of Oxi-ApoVs-loaded hydrogel microspheres promotes wound healing. Oxi-ApoV-loaded microspheres achieve controlled ApoV release, targeting ECs by reducing the consumption of inflammatory cells and adapting to the proliferative phase of wound healing. Thus, the biogenerated apoptotic vesicles responding to oxygen-related environmental stress can target ECs to promote vascularization., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Endothelial cell (EC) injury plays a key role in the chronic wound process. A long-term hypoxic microenvironment hinders the vascularization of ECs, thus delaying wound healing. In this study, CX3CL1-functionalized apoptotic body nanovesicles (nABs) were constructed. The "Find-eat" strategy was implemented through a receptor-ligand combination to target ECs that highly express CX3CR1 in the hypoxic microenvironment, therefore amplifying the "Find-eat" signal and promoting angiogenesis. Apoptotic bodies (ABs) were obtained by chemically inducing apoptosis of adipose-derived stem cells (ADSCs), and then functionalized nABs containing deferoxamine (DFO-nABs) were obtained through a series of steps, including optimized hypotonic treatment, mild ultrasound, drug mixing and extrusion treatment. In vitro experiments showed that nABs had good biocompatibility and an effective "Find-eat" signal via CX3CL1/CX3CR1 to induce ECs in the hypoxic microenvironment, thereby promoting cell proliferation, cell migration, and tube formation. In vivo experiments showed that nABs could promote the rapid closure of wounds, release the "Find-eat" signal to target ECs and realize the sustained release of angiogenic drugs to promote new blood vessel formation in diabetic wounds. These receptor-functionalized nABs, which can target ECs by releasing dual signals and achieve the sustained release of angiogenic drugs, may provide a novel strategy for chronic diabetic wound healing., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2023 Science China Press. Published by Elsevier B.V. All rights reserved.)

Schematic diagram of "Ludwigia sedioides" inspired substance-exchangeable spacer PTMS@P with PRP incorporated and its therapeutic effects for skin flap repair. [Display omitted] • A "Ludwigia sedioides" inspired ultra-thin microporous spacer is developed. • Slow-released growth factors from PRP strengthen revascularization and ECM synthesis. The spacer facilitates vascular shuttling and substance exchange. Extended vascular networks promoted skin flap survival and regeneration. Adequate substance exchange is an important prerequisite for tissue repair, and how to efficiently establish mature vascular networks to enhance the graft-host substance exchange is a challenge. Herein, inspired by the special structure of the aquatic plant "Ludwigia sedioides", ultra-thin microporous scaffolds (TMS) of bovine Achilles tendon derived collagen were fabricated as "floating leaves" via pyridine reaction, and cleverly combined with platelet-rich plasma (PRP) after the Schiff base and Michael additions reactions of polydopamine to construct a biomimetic "Ludwigia sedioides" spacer (PTMS@P), allowing blood vessels (as a "rhizome") freely shuttling and substance exchange. In this spacer, growth factors were efficiently released to peak concentrations in the first 12 h, thereby facilitating rapid blood vessel growth. In the subsequent 96 h, these slow-released growth factors retained at 11.6 % to 45.8 % of the peak concentrations, sustainedly promoting vascular networks shuttling through the spacer, graft-host substance exchange and extracellular matrix synthesis in fibroblasts. In vitro, the spacer significantly fostered fibroblasts and endothelial cells' proliferation, adhesion and migration, which were fundamental for revascularization and substance exchange. Immunohistochemical staining of CD31 and Ki67 in vivo demonstrated that abundant vascular networks shuttled through PTMS@P and extended from flap base to the farther flap body, promoting more robust substance exchange and cellular metabolism, which significantly enhanced the survival of ischemic flaps in nude mice. Altogether, this "Ludwigia sedioides" inspired spacer PTMS@P with strengthened revascularization and substance-exchange functionality holds promising applications for tissue repair and regeneration. [ABSTRACT FROM AUTHOR]