Bee ovum-inspired hydrogel programs microenvironment remodeling for diabetic wound healing

Abstract

Chronic diabetic wounds heal poorly due to a persistently imbalanced microenvironment involving inflammation and bacterial infection. Notably, oxidative stress, driven by mitochondrial damage, perpetuates inflammation and hinders repair. Existing therapeutic materials struggle to simultaneously address infection, inflammation, and oxidative stress through combined drug delivery and targeted activation of mitophagy. To tackle these intertwined challenges, we designed a bee ovum-inspired hydrogel (BOV) that mimics the parasitic wasp egg strategy, firm host adhesion and staged bioactive secretion, to programmatically remodel the wound microenvironment. The BOV consists of a borate-ester-crosslinked hyaluronic acid network providing robust wet adhesion and self-healing properties. It encapsulates gelatin-coated ZIF-8@Myricetin (Myr) nanoparticles and polyhexamethylene biguanide (PHMB), which are released sequentially in response to the wound's acidic, high-reactive oxygen species (ROS), and high-matrix metalloproteinase-9 (MMP-9) microenvironment: PHMB first exerts antibacterial action to control infection, followed by Myricetin release to scavenge ROS and suppress inflammation. Beyond antioxidant effects, BOV further activates the SIRT1/FOXO3a/BNIP3 pathway to promote mitophagy, clearing damaged mitochondria and thereby mitigating oxidative stress at its source. In vivo, BOV reduced bacterial burden, alleviated inflammatory response, and enhanced collagen deposition, and re-epithelialization. This study translates a natural parasitic strategy into a programmable drug-delivery platform, offering a promising approach for refractory diabetic wound therapy through microenvironment-responsive sequential treatment and upstream mitochondrial homeostasis restoration.