Mitochondrial dysfunctions cause many human disorders. In the recent years, targeting mitochondria emerged as an attractive strategy to control mitochondrial dysfunction related diseases. Despite the desire to direct therapeutics to the mitochondria, the actual task is more difficult due to the highly complex nature of the mitochondria. A platform technology for carrying bioactive molecules to different mitochondrial compartments could be of enormous potential benefit in medicine. Only a handful of nanoparticles (NPs) based on metal oxides, gold nanoparticles, dendrons, carbon nanotubes, and liposomes were recently engineered to target mitochondria. Most of these materials face tremendous challenges when administered in vivo due to their limited biocompatibility. We are developing hybrid biodegradable NP systems for their potential use in organelle targeting, combination therapy of cancer, combined neuroprotectatnt-stem cell therapy of neurodegenerative diseases, and image-guided therapy of atherothrombotic vascular diseases. We are developing rationally designed, programmable NP platform for diagnosis and targeted delivery of therapeutics for mitochondrial dysfunction related diseases. An optimized formulation for maximal mitochondrial uptake was identified through in vitro screening of a library of charge and size varied NPs and the uptake was studied by qualitative and quantitative investigations of cytosolic and mitochondrial fractions of cells treated with mitochondria-targeted blended NPs. The versatility of this platform was demonstrated by studying a variety of mitochondria-acting therapeutics for different applications. These include mitochondria targeting chemotherapeutics for cancer, mitochondrial antioxidant for diseases of central nervous system, and mitochondrial uncoupler for obesity. On the cardiovascular front, we are developing a long-circulating hybrid NPs that can mimic the properties of high-density lipoprotein in the management of vascular diseases.