Biomimetic Coacervates Protocells for Dual Delivery Pathways and Apoptosis/Pyroptosis Based Drug‐Free Therapeutics

Abstract Current drug delivery still faces the challenge of limited capacity of loading cargos and the risk of undesired drug leakage before reaching the target sites, limiting its therapeutic efficacy. As an alternative, liquid‐liquid phase separation‐based coacervates protocells may facilitate cellular uptake and improve organelle‐targeted delivery efficiency. Here, a drug‐free protocell system is proposed by using peptide‐polyphenol network shells wrapped nucleic acid coacervates (NC@PPNs), which can specifically and sequentially target breast cancer cells and their organelles. The rapid cellular uptake behaviors of NC@PPNs are found through both endocytosis and cholesterol‐dependent pathways. NC@PPNs may induce decreasing mitochondrial membrane potential, increasing intracellular ROS levels, and decreasing ATP levels, eventually inhibiting cell migration and apoptosis by mitochondria dysfunction. Interestingly, NC@PPNs can also induce endoplasmic reticulum swelling and trigger pyroptosis pathways. The cell death mechanism is evidenced by RNA sequencing analysis. Eventually, the dual cell death routines by NC@PPNs enhance the in vivo anti‐tumor efficacy. This strategy may open a new avenue in the field of drug‐free tumor therapy by nanoscale coacervates.