Harnessing engineered adaptive nanoparticles to modulate macrophages for treating corneal alkali burns

Corneal alkali burns represent a severe ophthalmic emergency characterized by progressive inflammation, impaired epithelial regeneration, and pathological neovascularization, posing significant clinical challenges. Conventional topical therapies are hindered by rapid precorneal clearance and limited corneal penetration. To overcome these limitations, we designed adaptive nanoparticles (PDNPs) formed by the self-assembly of polysialic acid (PSA)-dexamethasone (Dex) via acid-sensitive hydrazone linkages. Upon topical administration, PSA-mediated Siglec-E recognition enabled selective anchoring of PDNPs to infiltrating corneal stromal macrophages, which then undergo chemotaxis-directed migration into deeper inflamed tissues, enhancing ocular surface retention and drug penetration. In the acidic microenvironment of the injured cornea, PDNPs undergo controlled Dex release, enabling precise spatiotemporally modulation of macrophages. In mice model of alkali injury, PDNPs significantly prolonged ocular surface retention and improved stromal drug distribution. Moreover, the treatment of PDNPs remarkedly accelerated corneal re-epithelialization, restored stromal transparency, reduce corneal edema and inhibit neovascularization. Mechanistic study indicated that PDNPs alleviated the corneal injury by effectively inhibited of the MAPK/NF-κB signaling pathway, a key axis in corneal inflammation. Overall, PDNPs demonstrated excellent therapeutic efficacy and tolerability for potential application as a novel platform for modulating inflammatory ocular surface diseases.