M2-Type Macrophage Membrane-Mediated Delivery of Carvedilol Nanocomplex for Acute Liver Failure Treatment and Remodeling Inflammatory Microenvironment

Background: Interactions of hepatic macrophages with local inflammatory microenvironment is the key factor promoting the development of acute liver failure (ALF). Hence, reprogramming pro-inflammatory M1 into anti-inflammatory M2 phenotype may offer a promising strategy for treating ALF by targeting inflammation. Our group found Carvedilol possessed potential anti-inflammatory property previously, which had been scarcely reported in ALF.Methods: We present a synergy strategy to induce macrophages into the phenotype M2-type anti-inflammatory macrophages with IL-4 and IL-10 at first. Then carvedilol is loaded on the macrophage membrane-camouflaged biomimetic nano-platform (termed as M2M@CNP) to evade RES and afford carvedilol delivery to the inflammatory environment with overproduced ROS, further prolonging its circulation and accumulation. Cell-based experiments and preclinical models were used to evaluated the biocompatibility, side effects, targeting and therapeutic efficacy, and M1/M2 repolarization ability.Findings: M2-type macrophage membrane-camouflaged biomimetic nanocomplexes effectively targeted and accumulated in liver injured lesions and inflammatory environment. M2-CM endows nanocomplex with good immune escape and long circulation time. Sustainably released Carvedilol produced anti-inflammatory, antioxidant and anti-apoptosis effects, combining local M2-CM inhibited pro-inflammatory cytokines and ROS levels, which in turn promoted and amplified M1 to M2 phenotype polarization efficiency.Interpretation: This study offers new insights into the rational design of biomimetic nanosystems for safe and effective ALF therapy to accelerate the clinical translation.Funding: This work was supported by grants from the Research Unit Project of Chinese Academy of Medical Sciences (2019-I2M-5-030), the Research Project of Jinan Microecological Biomedicine Shandong Laboratory (JNL-2022002A), and the Zhejiang Provincial Natural Science Foundation of China (LQ22H030009). Declaration of Interest: The authors declare that there are no competing interests to disclose related to this study.Ethical Approval: All the animal experiments were strictly in accordance with the National Institute Guide for the Care and Use of Laboratory Animals. The experimental protocols were approved by the Ethics Committee of the First Affiliated Hospital, School of Medicine, Zhejiang University (Ethics Code 2023-1452).