Macrophage-targeted lipid nanoparticles based on Dendron-like lipids deliver mTOR inhibitor to alleviate systemic lupus erythematosus

The dysregulation of the Mammalian Target of Rapamycin (mTOR) pathway in immune cells is strongly associated with disease activity and the development of lupus nephritis in patients diagnosed with Systemic Lupus Erythematosus (SLE). However, oral rapamycin demonstrates considerable inter-individual variability in bioavailability, and prolonged exposure to this agent may induce a wide range of adverse effects. Nanodelivery systems represent a promising strategy to optimize the therapeutic efficacy of rapamycin in the treatment of SLE. Herein, we develop an advanced strategy for SLE therapy utilizing lipid nanoparticles (LNPs) based on dendron-like lipids (DL-lipids) that deliver rapamycin to macrophages of spleen and bone marrow. Initially, a DL-lipid library featuring a variety of functional moieties was synthesized. And LNPs composed of the DL-lipids were formulated and screened for targeting immune organs and cells. Particularly, the LNP incorporating trifluorinated DL-lipid C18 3F is capable of accumulating in the spleen and bone marrow in a time-dependent manner and demonstrates macrophage affinity in vivo . Meantime, the rapamycin-loaded C18 3F LNP (Rapa@C18-3F) exhibits a synergistic effect that suppresses the activity of Mechanistic Target of Rapamycin Complex 1 (mTORC1) within macrophages, which in turn attenuates the progression of SLE by limiting immune activation, facilitating autophagosome degradation, and promoting macrophage polarization. Furthermore, the rapamycin resistance caused by repeated administration was reversed with the use of Rapa@C18-3F. Consequently, this approach presents a potential strategy for the treatment of SLE through the inhibition of the mTORC1 pathway by the administration of Rapa@C18-3F. • A series of unique dendron-like lipids (DL-lipids) was synthesized, and macrophage-targeted lipid nanoparticles (LNPs) based on these DL-lipids, particularly the C18 3F, were prepared. • C18 3F LNPs facilitated targeted Rapamycin delivery to macrophages of spleen and bone marrow, thus presenting promising potential in the treatment of autoimmune diseases. • Treatment with Rapa@C18-3F significantly mitigated lupus nephritis and skin • lesions in the Systemic Lupus Erythematosus (SLE) mouse model, and minimized the rapamycin resistance associated with repeated administration. • Rapa@C18-3F exhibited enhanced macrophage mTORC1 inhibition that promotes autophagic degradation and M2 polarization in vivo .