Enhancing\nGene Delivery to Breast Cancer with Highly\nEfficient siRNA Loading and pH-Responsive Small Extracellular Vesicles

Small extracellular vesicles (sEVs) are promising nanocarriers\nfor drug delivery to treat a wide range of diseases due to their natural\norigin and innate homing properties. However, suboptimal therapeutic\neffects, attributed to ineffective targeting, limited lysosomal escape,\nand insufficient delivery, remain challenges in effectively delivering\ntherapeutic cargo. Despite advances in sEV-based drug delivery systems,\nconventional approaches need improvement to address low drug-loading\nefficiency and to develop surface functionalization techniques for\nprecise targeting of cells of interest, all while preserving the membrane\nintegrity of sEVs. We report an enhanced gene delivery system using\nmultifunctional sEVs for highly efficient siRNA loading and delivery.\nThe integration of chiral graphene quantum dots enhanced the loading\ncapacity while preserving the structural integrity of the sEVs. Additionally,\nlysosomal escape is facilitated by functionalizing sEVs with pH-responsive\npeptides, fully harnessing the inherent homing effect of sEVs for\ntargeted and precise delivery. These sEVs achieved a 1.74-fold increase\nin cytosolic cargo delivery compared to unmodified sEVs, resulting\nin substantial gene silencing of around 73%. Our approach has significant\npotential to advance sEV-based gene delivery in order to accelerate\nclinical progress.