A Strontium-Engineered FAND with Ultrahigh NAD+ Loading for Targeted Therapy of Acute Lung Injury

Abstract Acute lung injury (ALI) remains a devastating respiratory syndrome, with high mortality and limited therapeutic options. Herein, we report the rational design of a lung epithelial cell membrane-camouflaged full-API nanodrug (FAND) that integrates three bioactive components─bioactive trace element strontium ions (Sr2+), essential coenzyme nicotinamide adenine dinucleotide (NAD+), and FDA-approved anti-inflammatory drug dexamethasone (DEX)─into a supramolecular nanoassembly (DSN FAND@LM) with 100 wt % active pharmaceutical ingredient (API) content. Within this architecture, Sr2+ functions as a pivotal coordination hub, bridging DEX and NAD+ to achieve an ultrahigh NAD+ loading of ∼66.5%, the highest reported to date for NAD+-based nanotherapeutics. The engineered lung epithelial membrane imparts an intrinsic inflammation-homing capability, enabling precise accumulation at injured pulmonary sites. Synergistic therapeutic actions are realized through Sr2+-mediated regulation of apoptosis-associated signaling, NAD+-driven restoration of mitochondrial bioenergetics and suppression of NF-κB activation, and DEX-induced attenuation of oxidative stress. Both in vitro and in vivo studies demonstrate pronounced suppression of inflammatory cascades and enhanced lung epithelial regeneration, culminating in the accelerated repair of injured alveolar tissue. This work establishes a paradigm for FAND that codeliver Sr2+ and NAD+ for targeted, multimodal therapy of ALI and highlights a broadly translatable platform for metal ion-enabled nanotherapeutics.