M2 Macrophage membrane-mediated biomimetic nanoparticles carrying ADAM9 siRNA alleviate renal inflammation and fibrosis via the AKT/NF-κB pathway

The chronic kidney disease (CKD) situation remains severe globally. The prevention and management of CKD continue to be long-term and challenging tasks. A disintegrin and metalloprotease 9 (ADAM9) is a key factor in the progression of fibrosis and acts through multiple mechanisms, making it an important target in the study of fibrotic diseases. Thus, therapeutic strategies targeting ADAM9 hold promise for treating fibrotic disorders. This study aimed to utilize nanoparticle complexes coated with macrophage membranes (designated M2M@NP complexes) to deliver small interfering RNAs (siRNAs) targeting ADAM9 expression in the kidney. This approach was intended to exert a therapeutic effect on the progression of kidney disease. In vivo imaging confirmed that the macrophage membrane carrier exhibited excellent inflammation-targeting properties. In vitro and in vivo characterization confirmed that M2M@NPs possessed superior transfection efficiency and safety. The experimental results indicated that M2M@NP-ADAM9 siRNA complexes effectively reduced ADAM9 expression, thereby inhibiting the protein kinase B (AKT)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and reducing Ras-related C3 botulinum toxin substrate 1 (RAC1) and tumor necrosis factor receptor-associated factor 6 (TRAF6) expression. These complexes also reduced macrophage infiltration and M1 polarization, leading to attenuated renal inflammation and fibrosis. Our findings suggest that the M2M@NP delivery system has broad potential for treating CKD.