Abstract

Cancer cells reprogram their metabolism to sustain uncontrolled proliferation, survive hostile 
microenvironments, and evade therapeutic stress. These metabolic adaptations ranging from aerobic glycolysis 
and glutamine addiction to altered lipid and redox metabolism represent exploitable vulnerabilities for precision 
oncology. However, conventional metabolic inhibitors often suffer from poor bioavailability, systemic toxicity, 
and limited tumor selectivity. Self-assembling nanotherapeutics have emerged as a transformative strategy to 
overcome these limitations by integrating drug delivery, targeting, and therapeutic function within 
programmable nanoscale architectures. Through non-covalent interactions such as hydrophobic forces, 
hydrogen bonding, electrostatic attraction, and π–π stacking, small molecules, peptides, and polymers can 
spontaneously organize into functional nanostructures that respond to tumor-specific biochemical cues. This 
review critically examines the design principles, mechanisms, and therapeutic potential of self-assembling 
nanotherapeutics for targeting cancer metabolic vulnerabilities. We discuss how these systems enhance selective 
delivery of metabolic inhibitors, enable combinatorial and multi-pathway modulation, and exploit the unique 
metabolic and microenvironmental features of tumors. Current preclinical advances, emerging clinical prospects, 
and key translational challenges are also highlighted. Collectively, self-assembling nanotherapeutics represent 
a promising frontier for precision cancer metabolism–based therapies.