Inflammation-Triggered Andrographolide Nanoprodrug Platform for Lung-Targeted Delivery and Immune Homeostasis Recovery: A Therapeutic Strategy Against Cytokine Storm

Acute lung injury (ALI) leads to severe pulmonary inflammation and alveolar-capillary barrier disruption, with therapy limited by poor solubility and bioavailability of anti-inflammatory agents. To address the limited aqueous solubility, insufficient lesion accumulation, and poor bioavailability of andrographolide (ANDRO) in ALI therapy, an inflammation-responsive nanoprodrug platform (NanoPro5000@ANDRO) was developed via subcomponent self-assembly using dynamic boronic ester and imine linkages, thereby enabling both chemical conjugation and physical encapsulation of ANDRO at a total drug-loading content of 30.24% with an average hydrodynamic diameter of 206.4 nm. This platform exhibited excellent biocompatibility, including a hemolysis rate of less than 5% and protein adsorption of less than 10%, and achieved 82.1% cumulative ANDRO release at 48 h under acidic and oxidative conditions, facilitating inflammation-associated lesion-specific drug delivery. Furthermore, the nanosystem exhibited enhanced pulmonary accumulation in inflamed lung tissues, suppressed pro-inflammatory cytokines, including tumor necrosis factor-α and interleukin (IL)-6, upregulated anti-inflammatory mediators, including IL-4 and IL-10, reduced oxidative stress, and promoted M2 macrophage polarization. These combined effects alleviated cytokine storm, restored inflammatory microenvironment homeostasis, and attenuated lipopolysaccharide-induced ALI-associated tissue damage with confirmed biosafety. Overall, this study presents a dual dynamic covalent bond-based nanoprodrug strategy featuring dual ANDRO loading and pH/reactive oxygen species-responsive release behavior, providing a promising therapeutic approach for cytokine-associated inflammatory pulmonary diseases.