Engineering Resatorvid-Loaded Sub-Microgels of Epigallocatechin-3-gallate/Hyaluronic Acid to Treat Acute Lung Injury

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remain life-threatening conditions with high morbidity and mortality, largely due to excessive reactive oxygen species (ROS) generation and uncontrolled inflammatory cascades. Despite extensive pharmacological investigations, effective and targeted therapies are still lacking. This study develops an innovative hyaluronic acid (HA)-epigallocatechin gallate (EGCG)-amino phenylboronic acid (PBA) based sub-microgel (HAEP sub-microgel) platform capable of integrating multiple dynamic interactions (esterification, boronic ester bonds, and hydrogen bonding) to achieve stability, lung delivery, and antioxidant activity. The HAEP sub-microgel system is employed to deliver the anti-inflammatory agent resatorvid (Res) to the injured lung in a bleomycin-induced ALI mouse model. The HAEP@Res sub-microgels (0.1-1.4 µm) exhibit excellent biocompatibility, effectively scavenge intracellular ROS in human lung fibroblasts in vitro. Moreover, the HAEP@Res intratracheal administration significantly reduces histopathological lung tissue injury, and suppresses pro-inflammatory cytokine secretion (TNF-α, IL-6, IL-1β) and gene expression (Tlr4, Tnf, Il6, Il1b, Nrf2, Nos2, Tgfb, Ccl2) in vivo. Altogether, this study establishes a versatile HAEP sub-microgel-based drug delivery system for anti-inflammatory payloads, effectively alleviating lung inflammation and promoting ALI recovery, thereby demonstrating therapeutic potential for ALI/ARDS and other inflammation-related diseases.