Mitochondrial fusion targeted supramolecular peptide hydrogel for gut neuroprotection.

Oxidative stress-induced enteric neuropathy is a key driver of slow-transit constipation (STC), primarily through disrupted mitochondrial dynamics and neuronal degeneration. To address this, we developed a bioengineered oral delivery system that supports neuronal recovery and actively enhances mitochondrial membrane fusion. A self-assembling amphiphilic peptide (GFF) was synthesized to encapsulate rhein (RH), a natural anthraquinone with antioxidant, anti-inflammatory, and microbiota-regulating properties. A BDNF-derived tetrapeptide was integrated to further potentiate neurotrophic effects. These components were co-assembled into a therapeutic nanofiber (RFI), which was embedded in a chitosan/sodium alginate hydrogel for sustained oral delivery. In vitro and in vivo studies demonstrated that RFI significantly improved neuronal viability and gastrointestinal motility. Mechanistic investigations revealed that RFI is associated with activation of the AKT signaling pathway and enhancement of mitochondrial membrane fusion, collectively contributing to the restoration of mitochondrial network integrity and neuronal protection. This multifunctional nanoplatform offers a promising therapeutic approach to STC by combining targeted delivery with direct modulation of mitochondrial function.