Cholesterol-Based Lipid Nanoparticles as an Intracellular Drug Reservoir for Enhanced Tumor Therapy

Objective Cancer remains a critical public health challenge. Conventional anti-tumor drugs are often limited by their short half-life and the requirement for frequent and/or high-dose administration, highlighting the urgent need for drug delivery systems that can enhance intracellular drug accumulation. Methods Given that current research on drug delivery systems primarily focuses on developing active or passive targeting strategies to improve therapeutic efficacy, biocompatible cholesterol-based lipid nanoparticles (Cls-LNPs) were developed in this study. The Cls-LNPs were designed to function as an "intracellular drug reservoir" by enhancing cellular uptake and retention, thereby meeting the core requirement of enhanced intracellular drug accumulation. Results The reservoir capacity is likely attributed to the ability of Cls-LNPs to evade lysosomal degradation and target the endoplasmic reticulum (ER). When combined with the emerging anti-tumor technology of photodynamic therapy (PDT) and utilizing Ce6 as a model photosensitizer, the prepared Ce6@Cls-LNPs exhibited enhanced anti-tumor efficacy both in vitro and in vivo compared to free drugs. The therapeutic effect was achieved through the induction of ER stress, lipid peroxidation, and apoptosis, and it also exhibited a “bystander effect”. Conclusion This study offers valuable insights into the application of cholesterol in drug delivery systems and proposes innovative strategies for the development of retention-enhancing formulations. Graphical