Targeting nonapoptotic pathways with functionalized nanoparticles for cancer therapy: current and future perspectives.

Apoptotic death evasion is a hallmark of cancer progression. In this context, past decades have witnessed cytotoxic agents targeting apoptosis. However, owing to cellular defects in the apoptotic machinery, tumors develop resistance to apoptosis-based cancer therapies. Hence, targeting nonapoptotic cell-death pathways displays enhanced therapeutic success in apoptosis-defective tumor cells. Exploitation of multifunctional properties of engineered nanoparticles may allow cancer therapeutics to target yet unexplored pathways such as ferroptosis, autophagy and necroptosis. Necroptosis presents a programmed necrotic death initiated by same apoptotic death signals that are caspase independent, whereas autophagy is self-degradative causing vacuolation, and ferroptosis is an iron-dependent form driven by lipid peroxidation. Targeting these tightly regulated nonapoptotic pathways may emerge as a new direction in cancer drug development, diagnostics and novel cancer nanotherapeutics. This review highlights the current challenges along with the advancement in this field of research and finally summarizes the future perspective in terms of their clinical merits.