Transforming Small-Molecule Nanoaggregation into Functional Drug Delivery Platforms

The development of stimuli-responsive nanoaggregates offers a transformative approach to cancer therapy, addressing the challenges of selectivity and efficacy. The spontaneous formation of nanoscale aggregates of small organic molecules through self-assembly is a major hurdle in early-stage drug discovery. However, this disadvantage can be transformed with a meticulous design into a functional drug delivery platform. Here, we report <b>Nano-CC1-Acl</b>, a nanoaggregate engineered for targeted anticancer activity. <b>CC1</b> and <b>CC1-Acl</b>, benzimidazole derivatives, undergo self-assembly in aqueous environments to generate <b>Nano-CC1</b> (235.2 ± 28.2 nm; IC₅₀ > 100 μM) and <b>Nano-CC1-Acl</b> (110.6 ± 23.1 nm; IC₅₀ = 2.88-3.40 μM) nanoaggregates. The IC₅₀ value of <b>Nano-CC1-Acl</b> further decreases to 0.20 ± 0.16 μM in the presence of cysteine, a biothiol. Triggered by intracellular biothiols, <b>Nano-CC1-Acl</b> disassembles to release <b>CC1</b>, a potent microtubule-targeting agent that disrupts microtubule polymerization. Results presented here indicate that small molecule nanoaggregation can be utilized to develop functional drug delivery platforms.