Lipid Remodeling and Metabolic Adaptation in Cancer Cell Membranes: A Platform for Membrane-Targeted Nanotherapy.

Metabolic reprogramming in cancer cells induces profound alterations in membrane lipid organization, affecting phospholipid distribution, surface charge, and overall lipid composition. These modifications contribute to key oncogenic processes, including tumor progression, immune evasion, and resistance to therapy. Importantly, they also give rise to distinct biophysical features that may serve as selective targets for therapeutic intervention. Among these, the externalization of anionic phospholipids and the overexpression of negatively charged glycoconjugates render cancer cell membranes particularly susceptible to cationic membrane-active agents. Cationic anticancer peptides (ACPs) and their synthetic mimics (SMACPs) have emerged as promising candidates for selectively disrupting malignant membranes; however, limitations related to stability, bioavailability, and toxicity have restricted their clinical utility. To address these challenges, nanotherapeutic platforms-particularly dendrimers-have emerged as promising tools to enhance peptide delivery, enable precise targeting, and support multifunctional therapeutic strategies. Dendrimers, including the most recent class of polyurea (PURE) dendrimers, feature modular and biodegradable architectures that enable concurrent drug delivery, gene silencing, and imaging functionalities. This chapter examines how membrane lipid remodeling contributes to cancer pathophysiology and highlights recent advances in dendrimer-based nanocarriers as precision tools for exploiting membrane-associated vulnerabilities in oncology.