Biomimetic self-assembled nanosoldiers of paotianxiong polysaccharides and α-lipoic acid: Highly specific targeted therapy for mesangial proliferative glomerulonephritis

As a highly prevalent condition in Chronic Kidney Disease progression, mesangial proliferative glomerulonephritis (MsPGN) has limited therapeutic options, with the glomerular barrier substantially restricting drug efficacy. Reactive oxygen species (ROS), inflammation, and aberrant cellular proliferation play pivotal roles in the pathogenesis of MsPGN. To overcome limitations of conventional drugs and nanocarrier delivery systems in MsPGN treatment, this study proposed an interesting "drug-carrier integration, synergistic targeting' strategy. Our preliminary experiment found that Paotianxiong Polysaccharides (PP) has the effect of inhibiting mesangial cells (MCs) proliferation. Novel self-assembling nanoparticles incorporating hydrophilic PP and hydrophobic α-lipoic acid (LA) were developed. This design integrates the ROS scavenging and anti-inflammatory functions of LA with the superiority of PP in inducing MCs Apoptosis, thereby synergistically inhibiting the abnormal proliferation of MCs and improving bioavailability simultaneously. For the first time, nanoparticles were coated with LPS/PDGF-BB-activated MC membranes for biomimetic delivery, enabling targeted MsPGN therapy. The prepared nanoparticles (average size: 74 nm) demonstrated significant uptake in MCs. In vitro, they exhibited remarkable capabilities in inhibiting MCs proliferation, scavenging ROS, and reducing inflammation. In vivo, they can achieve the synergistic effect of active and passive targeting and effectively accumulate in glomerular MCs. Through the synergistic effects of regulating oxidative stress, inhibiting M1 macrophage polarization, and suppressing growth factor expression, they can effectively alleviate MsPGN. Furthermore, no significant adverse effects were observed during treatment. Overall, this study constructed a novel self-assembled nanoformulation for MsPGN treatment, provided a new and promising biomimetic nano-delivery strategy targeting glomerular MCs.