Carrier-free dual-drug nanoplatforms cooperatively remodel macrophage and VSMC fate specifications for treating abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a cardiovascular disease with extremely high mortality rate, yet its treatment options are still limited in the clinic. This study presents a carrier-free dual-drug nanoplatform to therapeutically reprogram macrophage fate for improving AAA treatment efficacy. The nanoplatform was synthesized through the self-assembly of naringenin (NGN) and rapamycin (RAP) and modified with DSPE-PEG 2K and DSPE-PEG 2K -cRGD (named RNR NPs) to confer AAA targeting capability. The RNR NPs could efficiently accumulate in AAA site after systemic administration for on-demand delivery of the NGN/RAP drug combination to vascular smooth muscle cells (VSMCs) and residing M1-like macrophages. Here the NGN and RAP components could cooperatively activate the transcription factor EB (TFEB) signaling in the AAA-residing pro-inflammatory M1-like macrophages to reprogram them into an anti-inflammatory M2-like phenotype to reverse local inflammation. Meanwhile, they could also scavenge reactive oxygen species in VSMCs and inhibit apoptosis signaling to inhibit VSMCs apoptosis and calcification. These effects could act in a cooperative manner for effectively ameliorating AAA symptoms in vivo . Overall, the RNR NPs present an approach for the efficient treatment of AAA in the clinic with optimal safety.