Carrier-free targeted co-assembly of glycyrrhizin and puerarin overcomes ocular barriers for corneal alkali burn therapy via macrophage reprogramming

Corneal alkali burns (CAB) represent a devastating form of ocular trauma characterized by the rapid penetration of alkaline agents, triggering a destructive cascade of inflammatory infiltration, neovascularization, and fibrotic remodeling that compromises ocular transparency. Current pharmacological interventions are largely palliative and severely hampered by rapid precorneal clearance and poor epithelial penetrability. To overcome these formidable dynamic and static ocular barriers, we engineered a carrier-free, targeted nanoplatform via the spontaneous co-assembly of natural bioactives glycyrrhizin (GA) and puerarin (PUE), surface-functionalized with cyclic arginine-glycine-aspartic acid (GP@cRGD NPs). The GP@cRGD NPs exhibited robust physicochemical stability and rapid release kinetics precisely tailored for acute trauma intervention. Crucially, cRGD modification significantly enhanced precorneal retention and trans-epithelial penetration via integrin-targeted interactions. In vivo evaluations demonstrated that topical administration of GP@cRGD NPs markedly accelerated epithelial regeneration, suppressed pathological neovascularization, and successfully restored corneal optical clarity in a murine CAB model. Mechanistically, in vivo transcriptomic profiling and immunofluorescence corroborated that this nanomedicine synergistically reprogrammed the local immune microenvironment by directly inhibiting M1 macrophage polarization and extinguishing downstream pro-inflammatory and pro-fibrotic signaling cascades. Ultimately, this study demonstrates that our targeted, multi-mechanistic nano-formulation holds substantial promise for clinical translation, emerging as a powerful therapeutic intervention against severe chemical burns of the eye.