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Mitochondria are among the most dynamic organelles regulating a wide array of cellular processes. They are the cellular hub for oxidative phosphorylation, energy production, and cellular metabolism, and they are important determinants of cell fate, as they control cell death/survival pathways. The mitochondrial network plays a critical role in cellular inflammatory responses, and mitochondria are central in many pathologic conditions such as chronic inflammatory and aging-associated degenerative diseases. Recent advancements in our understanding of the pathogenic pathways and the role of mitochondria therein have identified highly specific therapeutic targets in order to develop personalized nanomedicine approaches for treatment. A wide array of nanoparticle-based formulations has been employed for potential usage in both diagnosing and treating chronic and fatal conditions, with gold nanoparticles and liposomal encapsulation being of particular interest. In this review, we highlight and summarize the advantages and challenges of developing these nanoformulations for targeted and spatiotemporally controlled drug delivery. We discuss the potential of nanotherapy in neoplasms to target the mitochondrial regulated cell death pathways and recent seminal developments in liposomal nanotherapy against chronic inflammatory lung diseases. The need for further development of nanoparticle-based treatment options for neuroinflammatory and neurodegenerative conditions, such as Alzheimer's disease (AD), is also discussed.