A nano-bioconjugate modified with anti-SIRPα antibodies and antisense oligonucleotides of mTOR for anti-atherosclerosis therapy

Atherosclerosis is the main cause of a series of fatal cardiovascular diseases, characterized by pathological accumulation of apoptotic cells and lipids. Pro-phagocytic antibody-based or pro-autophagy gene-based therapies are currently being explored to stimulate the phagocytic clearance of apoptotic cells and lipid metabolism; however, monotherapies are only moderately effective or require high doses with unacceptable side effects. Herein, we engineered a specific nano-bioconjugate loaded with antisense oligonucleotides (ASOs) of mammalian target of rapamycin (mTOR) and modified with anti-signal-regulated protein-α antibody (aSIRPα) for macrophage-mediated atherosclerosis therapy. The specific nano-bioconjugate utilized acid-responsive calcium phosphate (CaP) as a carrier to load mTOR ASOs, coated with lipid on the surface of CaP nanoparticles (ASOs@CaP), and subsequently modified with aSIRPα. The resulting nano-bioconjugates could accumulate within atherosclerotic plaques, target to macrophages and reactivate lesional phagocytosis through blocking the CD47-SIRPα signaling axis. In addition, efficient delivery of mTOR ASOs inhibited mTOR expression, which significantly restored impaired autophagy. The combined action of mTOR ASOs and aSIRPα reduced apoptotic cells and lipids accumulation. This nanotherapy significantly reduced plaque burden and inhibited progression of atherosclerotic lesions. These results show the potential of specific nano-bioconjugates for the prevention of atherosclerotic cardiovascular disease. STATEMENT OF SIGNIFICANCE: Atherosclerosis is the main cause of a series of fatal cardiovascular diseases. Pro-phagocytic antibody-based or pro-autophagy gene-based therapies are currently being explored to stimulate the phagocytic clearance of apoptotic cells and lipid metabolism; however, monotherapies are only moderately effective or require high doses with unacceptable side effects. Herein, we engineered a specific nano-bioconjugate loaded with antisense oligonucleotides (ASOs) of mammalian target of rapamycin (mTOR) and modified with anti-signal-regulated protein-α antibody (aSIRPα) for macrophage-mediated atherosclerosis therapy. Our study demonstrated that the combined action of mTOR ASOs and aSIRPα reduced apoptotic cells and lipids accumulation. This nanotherapy significantly reduced plaque burden and inhibited progression of atherosclerotic lesions. These results show the potential of specific nano-bioconjugates for the prevention of atherosclerotic cardiovascular disease.