Self-Assembling Nanotherapeutics for Precision Targeting of Cancer Metabolic Vulnerabilities
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 anotherapeutics 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. Keywords: cancer metabolism; self-assembly; nanotherapeutics; metabolic vulnerabilities; precision oncology.