Macrophage Membrane-Cloaked ROS-Responsive Albumin Nanoplatforms for Targeted Delivery of Curcumin to Alleviate Acute Liver Injury.

Developing low-toxicity, high-efficacy, and fast-acting strategies to manage acute liver injury (ALI) is critical due to its rapid progression and potential for severe outcomes. Curcumin (CUR) has shown promise in ALI therapy due to its ability to modulate the inflammatory microenvironment by scavenging reactive oxygen species (ROS). Nevertheless, CUR is highly hydrophobic limiting its bioavailability and effective in vivo transport, which hinders its further application. In this study, we developed an inflammatory microenvironment-targeted drug delivery system by covalently coupling human serum albumin (HSA) with ROS-sensitive thioketal linkers and loading it with CUR to form nanoparticles (HSA-TK/CUR). These nanoparticles were then coated with a macrophage membrane (CM@HSA-TK/CUR), resulting in negatively charged spherical particles (≈ -23.26 mV) with an average particle size of around 165 nm. ROS responsiveness was confirmed through drug release assays and enhanced ROS depletion was further demonstrated by Diacetyldichlorofluorescein (DCFH-DA) ROS detection experiments. CM@HSA-TK/CUR treatment resulted in a 94.7% reduction in ROS levels in inflammatory cells. In addition, cellular uptake and in vivo distribution experiments demonstrated that camouflaging HSA-TK/CUR with macrophage membranes significantly enhanced its targeting of the inflammatory microenvironment. The findings revealed that CM@HSA-TK/CUR rapidly accumulated in the injured liver within 6 h, inhibited the production of pro-inflammatory factors (IL-1β, IL-6, and TNF-α), shifted macrophage polarization from M1 to M2 in vivo, and protected hepatocytes from oxidative stress-associated cell death, significantly attenuating the inflammatory response in ALI mice. In conclusion, CM@HSA-TK/CUR has excellent potential in treating mice with ALI.