No abstract

Thin endometrium is a primary cause of failed embryo transfer, resulting in long‐term infertility and negative family outcomes. While hormonal treatments have greatly improved fertility results for some women, these responses remain unsatisfactory due to damage and infection of the complex endometrial microenvironment. In this study, a multifunctional microenvironment‐protected exosome‐hydrogel is designed for facilitating endometrial regeneration and fertility restoration via in situ microinjection and endometrial regeneration. This exosome hydrogel is formulated via Ag+‐S dynamic coordination and fusion with adipose stem cell‐derived exosomes (ADSC‐exo), yielding an injectable preparation that is sufficient to mitigate infection risk while also possessing the antigenic contents and paracrine signaling activity of the ADSC source cells, enabling regeneration of the endometrial microenvironment. In vitro, this exosome‐hydrogel exerts an outstanding neovascularization‐promoting effect, increased human umbilical vein endothelial cell proliferation and tube formation for 1.87 and 2.2 folds. In vivo, microenvironment‐protected exosome‐hydrogel also reveals to promote neovascularization and tissue regeneration while suppressing local tissue fibrosis. Importantly, regenerated endometrial tissue is more receptive to give embryos and birth to a healthy newborn. This microenvironment‐protected exosome‐hydrogel system offers a convenient, safe, and noninvasive approach for repairing thin endometrium and fertility restoration.

A break of extracellular matrix (ECM) balance can cause several degenerative changes in soft tissues. To reverse the imbalance fundamentally, a recently developed treatment, gene therapy, came to attention. However, the efficiency of the approach is limited because long‐term localized presence and bioactivity are difficult to achieve. Here, reconstituted lysyl oxidase‐like 1 (LOXL1) plasmids (pLOXL1) are loaded into nanoliposomes by a microfluidic chip, followed by encapsulation into the core layer of core–shell nanofibers by microsol‐electrospinning to achieve local accumulation and biological availability of the constructs and enable rapid ECM response. Results show that the pLOXL1‐Lipo@PLCL‐HA achieves the sustained release of pLOXL1 over a 30‐day period, with its transfection efficiency maintained above 50%. In a rabbit model of abdominal hernia, the long‐term collagen remodeling density is raised by over 90% in the pLOXL1‐Lipo@PLCL‐HA implanted animals compared to the control animals. The expression levels of ECM gene (COL1A1, COL3A1, Elastin, Fubilin5) are significantly increased. Collectively, this study establishes that pLOXL1‐Lipo@PLCL‐HA accelerates local ECM reconstruction via effective and reliable gene delivery as a potential base material of a “patch” for pelvic floor repairment, and identifies the key principles for design of LOXL1‐incorporated scaffolds for ECM regeneration.