Mitochondrial dysfunction in Alzheimer's disease: targeting the powerhouse with nanomedicine.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by relentless cognitive decline. Despite decades of research dominated by the amyloid and tau hypotheses, clinical interventions targeting these classical hallmarks have yielded limited success in halting disease progression, underscoring a critical conceptual and therapeutic gap: the early, persistent, and under-addressed role of mitochondrial dysfunction as a primary driver of AD pathology. Beyond serving as passive victims of amyloid-beta toxicity, impaired mitochondria actively initiate and perpetuate a self-amplifying cycle through dysregulated bioenergetics, aberrant dynamics, compromised quality control, calcium dyshomeostasis, and exacerbated neuroinflammation-all of which collectively propel synaptic loss and neuronal death well before overt plaque deposition. This review provides a synthesized reappraisal of this mitochondrial-centric paradigm, systematically delineating the interconnected nature of mitochondrial failure as both an initiator and an amplifier of AD and arguing that it represents a central nexus linking sporadic and genetic forms of the disease. We further consolidate the emerging landscape of nanomedicine as a revolutionary strategy to bridge the current therapeutic gap, highlighting how diverse nanotherapeutic platforms-ranging from organic and inorganic nanocarriers and biomimetic vesicles to nanozymes and gene-modulating systems-are uniquely equipped to overcome the blood-brain barrier and achieve subcellular precision targeting of the mitochondrial compartment. By analyzing advances in nanotechnology designed explicitly to restore mitochondrial homeostasis through the normalization of redox balance, enhancement of mitophagy, and preservation of adenosine triphosphate synthesis, we demonstrate how this approach directly addresses the root of the neurodegenerative cascade that traditional drug development has failed to reach. Finally, we critically examine the translational hurdles and future trajectories of mitochondria-targeted nanotherapy, proposing a conceptual framework for multidisciplinary integration and arguing that mitochondrial nanomedicine represents not merely a symptomatic intervention but a requisite disease-modifying paradigm shift capable of intercepting the earliest triggers of AD.