Rational design of imidazolium-functionalized liposomes for mitochondrial delivery: From amphiphile architecture to organelle-specific targeting.

Mitochondria are attractive targets for anticancer therapy because of their central role in cellular metabolism and apoptosis. Here, we report a series of hydroxypropyl-functionalized imidazolium surfactants (HPIm-n, n = 12, 14, 16, and 18) and their use as non-covalent modifiers of liposomal nanocarriers. The surfactants exhibited pronounced self-assembly behavior and low critical micelle concentrations. Incorporation of HPIm-n into liposomes produced stable nanosized particles (40-100 nm) with positive surface charge (zeta potential +20 to +49 mV) and long-term colloidal stability in aqueous media. The modified liposomes showed reduced nonspecific toxicity relative to the free surfactants while retaining activity against tumor cells. Confocal microscopy demonstrated enhanced mitochondrial-associated localization of HPIm-12-modified liposomes relative to unmodified liposomes, whereas JC-1 and caspase assays provided evidence consistent with mitochondrial dysfunction and involvement of the intrinsic apoptotic pathway. Doxorubicin-loaded liposomes exhibited sustained drug release, enhanced cellular uptake, and improved anticancer activity in selected tumor cell lines while generally showing lower toxicity toward normal cells. Together, these results identify hydroxypropyl-functionalized imidazolium surfactants as versatile building blocks for multifunctional, mitochondria-directed liposomal delivery systems and clarify relationships between amphiphile architecture and biological performance.