Hyaluronic acid engineered melanin-MOF nanoreactor synergistically remodeling redox and immune homeostasis for targeted acute lung injury therapy

Reactive oxygen species (ROS)-triggered oxidative stress, inflammatory responses, and overactivation of immune cells are critical factors exacerbating acute lung injury (ALI). Conventional clinical therapies are often limited by non-specificity, single-target limitations, and significant side effects to precisely modulate the complex pathological microenvironment. Here, we designed a hyaluronic acid-engineered nanoreactor (HA@MZ) through in situ encapsulation of melanin (MA) within ZIF-67, allowing multi-target synergistic therapy of ALI. The HA coating facilitates mucus penetration and targeted accumulation in injured lungs, exhibiting good biocompatibility. Under acidic inflammatory conditions, HA@MZ responsively releases MA, which efficiently scavenges ROS. This process activates Nrf2/HO-1 and GPX4 pathways while inhibiting NF-κB driven inflammation and M1 macrophage polarization, leading to reduced lipid peroxidation and recovery of redox and immune balance. Both in vitro and in vivo results confirm the lung microenvironment-balancing capacity of HA@MZ, offering a promising nanotherapeutic strategy for ALI and other inflammatory diseases.