Core–Shell Structured BPNS@Gel: A Smart-Responsive, Multimechanistic Nanotherapeutic for Dry Eye Disease

Dry eye disease (DED) is a prevalent ocular surface disorder driven by a self-perpetuating cycle of oxidative stress and inflammation, for which current therapies face limitations in bioavailability, retention, and multimechanistic action. To address this, we developed a core–shell structured BPNS@Gel platform, integrating a functionalized black phosphorus nanosheet (f-BPNS) core with a thermoresponsive hydrogel shell. The f-BPNS core (3–5 nm thick) was surface-modified with thiol groups and hyaluronic acid for mucoadhesion and corneal targeting, retaining superior multienzyme-mimetic activities (SOD: 5120 U/mg, CAT: 385 U/mg, GPx: 240 U/mg). The shell, composed of Pluronic F127/ N -isopropylacrylamide/chitosan, exhibited thermoresponsiveness (sol–gel transition at 37 °C, gelation time: 45 ± 3 s) and smart ROS/pH sensitivity (68.3% BPNS release under 100 μM H 2 O 2 ). In vitro, BPNS@Gel demonstrated excellent biocompatibility (>90% cell viability at f-BPNS ≤ 50 μg/mL), targeted corneal epithelial uptake, and multimechanistic action: it scavenged reactive oxygen species, reprogrammed macrophages from a pro-inflammatory M1 (CD86 +: 69.6% → 28.3%) to an anti-inflammatory M2 phenotype (CD206 +: 18.7% → 42.5%), and promoted corneal epithelial repair (89.3% thickness recovery) and goblet cell regeneration (85.6% density restoration). In a benzalkonium chloride-induced DED mouse model, BPNS@Gel significantly improved tear secretion (78.5% increase), tear film stability (tear breakup time: 8.5 s), and corneal integrity (65.2% reduction in fluorescein staining scores), with excellent long-term biocompatibility. This core–shell design exemplifies a paradigm shift in DED therapy, combining smart responsiveness, targeted delivery, and multimechanistic synergy. This work establishes a paradigm for smart, multitarget nanomedicines to restore ocular surface homeostasis, offering a promising clinical strategy for DED and related inflammatory ocular surface diseases.