Spatial targeting of Bcl-2 on endoplasmic reticulum and mitochondria in cancer cells by lipid nanoparticles

The presence of the same proteins at different sub-cellular locations with completely different functions adds to the complexity of signalling pathways in cancer. Subsequently, it becomes indispensable to understand the diverse critical roles of these proteins based on their spatial distribution for the development of improved cancer therapeutics. To address this, in this work, we report the development of endoplasmic reticulum (ER) and mitochondria targeted nanoscale particles to spatially impair anti-apoptotic Bcl-2 protein in these organelles in HeLa cervical cancer cells. Confocal microscopy and gel electrophoresis confirmed that these nanoparticles selectively home into ER and mitochondria and inhibited Bcl-2 localized there. Interestingly, Bcl-2 inhibition in ER induced ER stress leading to autophagy, whereas inhibition of Bcl-2 in mitochondria leads to mitochondrial damage and programmed cell death (apoptosis) in HeLa cells. These nanoscale platforms can be further explored as chemical biology tools to decipher the location-function relationship of proteins towards next generation cancer therapeutics.