Structure-Programmable DNA Assemblies Drive Mitochondrial Topological Remodeling via Steric Hindrance and Spatial Clustering.

In situ self-assembled nanotherapeutics offer a highly promising strategy for precision oncology. However, precisely driving subcellular interventions by tuning the macroscopic physical properties of materials remains a significant challenge. Here, a highly programmable DNA nanoplatform is developed to systematically elucidate the intrinsic link between material assembly morphologies and mitochondrial intervention modes. By integrating triphenylphosphine (TPP)-modified triangular prism frameworks with microRNA-triggered dynamic hybridization chain reactions (HCR), the precise manipulation of assembly network density and spatial distribution within living cells is achieved. Unlike traditional strategies relying on single-mode aggregation, quantitative analysis reveals that customized material assembly features dictate differentiated subcellular intervention modes. The in situ constructed highly crosslinked dense networks generate intense steric hindrance to drive profound physical fragmentation of mitochondria, manifested by decreases in area, form factor, and branching complexity. Alternatively, a temporally mediated localized assembly strategy actively induces massive spatial clustering of mitochondria. Both physical topology-driven intervention modes reliably trigger cascading metabolic dysfunctions, thereby significantly suppressing tumor growth in vivo. By revealing how specific structural parameters drive subcellular remodeling, this study provides a versatile engineering framework for the precise manipulation of organelles using programmable materials.