Promoting Re-epithelialization in an oxidative diabetic wound microenvironment using self-assembly of a ROS-responsive polymer and P311 peptide micelles

Engineering smart nano-therapeutics for re-epithelialisation of chronic wounds facilitates the wound healing process. However, due to excessive oxidative stress damage and persistent inflammation in diabetic wound microenvironment, the migration of stimulating epidermal cells in diabetic wounds represents a significant challenge. Here we synthesised P311-loaded micelles by self-assembly of P311 Peptides and diblock copolymer poly (ethylene glycol)-block-poly (propylene sulfide) (PEG-b-PPS, denoted as PEPS) that have unique ability to transform an oxidative wound microenvironment into a proregenerative one while also providing cues for epidermal cell migration. The P311@PEPS showed an accelerated migration of epidermal cells via activation of the Akt signalling pathway, simultaneously suppressing the unfavourable oxidative wound microenvironment by scavenging Reactive Oxygen Species (ROS), ultimately leading to the induction of an environment conducive to cell migration. Furthermore, the micelles were able to bypass the inhibitory effect of ROS on the Akt signalling pathway, thereby promoting epidermal cell migration. Additionally, we observed that diabetic wounds treated with P311@PEPS showed accelerated chronic wound healing, granulation tissue formation, collagen deposition and re-epithelialisation, thereby suggesting the efficacy of P311@PEPS as a promising nanoplatform for the treatment of chronic wounds. STATEMENT OF SIGNIFICANCE: Based on the unique conditions of the diabetic wound microenvironment, a smart drug delivery system with ROS-responsive nanomaterials has been widely investigated to enhance diabetic wound healing. In our previous studies, we observed that P311 promotes epidermal cell migration to induce wound re-epithelialisation. However, the application of P311 suffers from its instability. Herein, we developed a therapeutic platform with P311-loaded micelles (P311@PEPS), which were synthesized by the self-assembly of P311 Peptides and diblock copolymer poly (ethylene glycol)-block-poly (propylene sulfide) (PEG-b-PPS, denoted as PEPS). These micelles provide continuous migration signals for epidermal cells by ROS-trigged P311 release. Additionally, P311@PEPS scavenges excess ROS and provides a microenvironment that reduces inflammation, which could protect P311 from enzymatic degradation and improve the bioavailability of P311.