Lipid Remodeling in Cancer Cell Membranes Creates Nanotherapy Targets for Cationic Peptides and Dendrimers

Metabolic reprogramming in cancer cells profoundly alters membrane lipid organization, affecting phospholipid distribution, surface charge, and overall lipid composition. These modifications drive key oncogenic processes like tumor progression, immune evasion, and therapy resistance. Current cancer treatments often struggle with selectivity and overcoming resistance mechanisms. Exploiting distinct biophysical features of malignant membranes, such as externalized anionic phospholipids and overexpressed negatively charged glycoconjugates, presents a critical therapeutic gap for precision oncology.

This review synthesizes current understanding of cancer cell membrane lipid alterations, identifying distinct biophysical features that serve as selective therapeutic targets. It evaluates the potential of cationic membrane-active agents, including cationic anticancer peptides (ACPs) and their synthetic mimics (SMACPs), for selectively disrupting malignant membranes. The chapter further explores how nanotherapeutic platforms, particularly dendrimers, address the limitations of these agents, focusing on enhanced delivery, precise targeting, and multifunctional therapeutic strategies.

Cancer cells exhibit profound lipid remodeling, resulting in distinct biophysical features such as the externalization of anionic phospholipids and overexpression of negatively charged glycoconjugates. These alterations render malignant membranes particularly susceptible to cationic membrane-active agents. While cationic anticancer peptides (ACPs) and their synthetic mimics (SMACPs) demonstrate promise for selectively disrupting these membranes, their clinical translation is hindered by limitations in stability, bioavailability, and systemic toxicity. Nanotherapeutic platforms, specifically dendrimers, are highlighted as a crucial advancement to overcome these challenges. > Dendrimers, including the recent class of polyurea (PURE) dendrimers, feature modular and biodegradable architectures that enable enhanced peptide delivery, precise targeting, and support multifunctional therapeutic strategies, including concurrent drug delivery, gene silencing, and imaging functionalities. This approach leverages the unique vulnerabilities created by lipid remodeling to improve therapeutic efficacy and selectivity in oncology.