Lipid-based nanoparticles external triggered release strategies in cancer nanomedicine.

Nearly half of humanity will develop cancer in their Lifetime. Current therapies, particularly chemotherapeutic drugs, face significant challenges due to the lack of tissue-specific delivery. For example, less than 0.1% of anticancer drugs administered systemically reach the tumor site, resulting in damage to healthy tissues and leading to a wide range of side effects. An effective strategy to address this problem is the encapsulation of chemotherapeutic drugs within nanoscale synthetic lipid structures, known as lipid-based nanoparticles (LBNPs). LBNPs can enhance a drug's circulation half-life in the bloodstream and exploit the enhanced permeability and retention (EPR) effect. These delivery systems have led to the approval of more than 20 FDA-approved chemotherapeutic drugs. The greatest advantage is often improved pharmacokinetics, which enables a higher maximum tolerated dose while maintaining similar therapeutic efficacy and reducing side effects. However, a key limitation is that in many cases LBNPs are too stable, with free drug released very slowly, which limits anticancer efficacy. Consequently, externally triggered strategies have gained increasing attention, as they allow site-specific and on-demand release of LBNP contents at the tumor, thereby overcoming this stability barrier and enabling higher tumor-specific drug concentrations with fewer systemic side effects. This article reviews recent advances in externally triggered release mechanisms for LBNPs, including thermal, ultrasound, radiation, magnetic, and light-based approaches, and examines their potential integration into clinical cancer settings.