Abstract

 Obesity is increasingly understood as a brain-centric disorder in which hypothalamic circuits and the gut–brain 
axis fail to correctly integrate peripheral signals of energy status. Hypercaloric diets and adipose expansion 
drive leptin and insulin resistance, neuroinflammation and altered gut hormone signaling, leading to persistent 
hyperphagia and reduced energy expenditure. Existing anti-obesity drugs, including GLP-1 receptor agonists, 
modulate some of these pathways but are limited by systemic side effects, variable brain penetration and receptor 
desensitization. Nanotechnology offers new opportunities to deliver appetite-regulating agents directly and 
selectively to central and peripheral nodes of energy homeostasis. This review examines the neurobiology of 
hypothalamic appetite control and gut–brain communication, then outlines nanocarrier strategies for crossing 
the blood–brain barrier or using nose-to-brain and gut-to-brain routes. We discuss nano-enabled delivery of 
hormones, peptides and small molecules that modulate leptin, melanocortin, GLP-1 and inflammatory pathways, 
including approaches that rescue hypothalamic leptin signaling and dampen diet-induced neuroinflammation. 
Finally, we consider theranostic systems, safety and ethical issues, and prospects for integrating nanotechnology 
into precision appetite-targeted obesity therapy.