Biomimetic intelligent lipoprotein nanocarrier for sustained and well-tolerated nerve growth factor delivery in neurotrophic keratopathy treatment.

Neurotrophic keratopathy (NK) is a degenerative disease caused by trigeminal/corneal nerve damage and may progress to persistent epithelial defects, ulceration, perforation, and vision loss. Although recombinant human nerve growth factor (rhNGF) has been approved for NK treatment, its clinical use is limited by low ocular bioavailability, irritation, and frequent dosing (six times daily). Here, we developed a biomimetic intelligent enzyme-responsive lipoprotein (NGFc-L@P) for sustained and well-tolerated delivery of NGF. NGFc-L@P features (i) an outer shell of reconstituted high-density lipoprotein (rHDL) functionalized with matrix metalloproteinase-9 (MMP-9)-activatable cell-penetrating peptides, enabling lesion-responsive activation and enhanced corneal penetration; and (ii) an inner core that mimics the extracellular matrix and encapsulates NGF, preserving its bioactivity while providing sustained release. Compared with conventional NGF formulations, NGFc-L@P prolonged corneal NGF residence to >8 h, enabled sustained release, mitigated ocular irritation and enabled targeted penetration. In alkali burn-induced NK mouse models, NGFc-L@P markedly accelerated corneal epithelial healing, promoted nerve restoration and suppressed inflammation with three daily instillations. Besides, diabetes NK mice were established to further validate superior therapeutic efficacy and universality of NGFc-L@P. Collectively, this biomimetic intelligent lipoprotein nanocarrier provides a promising strategy for NK therapy in a multi-dimensional manner and holds strong potential for clinical translation.