Chirality and morphology-dependent siRNA delivery for targeted lung cancer therapy with intrinsically chiral gold nanoparticles

The clinical translation of RNA interference (RNAi) for lung cancer treatment remains hampered by the lack of delivery vectors that concurrently optimize cellular uptake, target specificity, and in vivo stability. This work reports an intrinsically chiral gold nanoparticle (Au NP) platform with precisely controlled morphology for targeted siRNA delivery. Through a full 2 × 2 factorial design (2 chiralities × 2 morphologies), the work decouples the individual and combined contributions of these two parameters. It is found that right-handed chiral nanoparticles (D-NPs) show significantly faster cellular internalization and higher gene silencing potency than left-handed (L-NPs) and achiral (DL-NPs) counterparts. Beyond chirality, nanoparticle morphology serves as an equally critical parameter: the rhombicuboctahedral (RCO) architecture yields markedly higher silencing efficacy than cubic counterparts with D-chirality. Furthermore, proteomic analysis revealed that Au RCO nanoparticles with different chirality displayed distinct functional enrichment profiles. By D-RCO combination with minimal surface modification, siRNA targeting PD-L1 achieves potent knockdown and robust inhibition of H460 lung cancer proliferation both in vitro and in vivo. This work establishes chirality and morphology as co-designable parameters for gene delivery and provides a mechanistic blueprint for translating chiral nanomaterials into solid tumor therapy.