All-in-one inflammation-targeted and immunomodulatory hollow mesoporous polydopamine nanoparticles for synergistic nephritis therapy

Nephritis-responsive dual-targeting HA-modified hollow mesoporous polydopamine nanoparticles for AKI combination therapy. • An all-in-one kidney-targeted system jointly alleviates oxidative stress, inflammation, and immune dysregulation. • The all-in-one system improves flavonoid solubility, bioavailability, and targeting, boosting efficacy and reducing toxicity. Acute kidney injury (AKI) is a severe syndrome driven by oxidative stress and inflammation, with limited effective drug therapy. Total flavonoids (Fla) from Abelmoschus manihot (L.) Medic have strong antioxidant and anti-inflammatory activity, but poor solubility and weak renal targeting limit its clinical translation. Here, a nephritis microenvironment-responsive dual-targeting nanoplatform (Fla@HMPDA@HA) was constructed by loading Fla into hyaluronic acid (HA)-modified hollow mesoporous polydopamine (HMPDA) nanoparticles. HMPDA provided high drug-loading capacity and intrinsic reactive oxygen species (ROS)-scavenging activity, enabling a synergistic therapeutic effect with Fla. Fla@HMPDA@HA could be efficiently internalized by injured renal tubular epithelial cells, reversed H 2 O 2 -induced oxidative injury, restored mitochondrial membrane potential, and reduced apoptosis. It also promoted macrophage polarization from an M1-like to an M2-like phenotype up to 43.35%, while significantly downregulating TNF-α, IL-6, and IL-1β. In vivo imaging confirmed preferential accumulation of HA-modified nanoparticles in damaged kidneys. After intravenous administration, Fla@HMPDA@HA preserved kidney structure, restored renal function, and alleviated local inflammation and apoptosis, thereby markedly attenuating LPS-induced AKI with negligible systemic toxicity. Overall, this dual-targeting platform integrates targeted delivery, anti-inflammatory activity, and immune microenvironment remodeling together, offering a promising therapeutic strategy for AKI.