Topology-controllable DNA framework-based nanocapsule enhances tumor suppression via adaptive modulation of lysosomal-mitochondrial axis.

The organelle crosstalk has proven as a promising focal point for tumor therapy, however, achieving its precise and adaptive regulation remains a significant challenge. Herein, we construct a DNA framework-based nanocapsule encapsulated with DNA-templated silver nanoclusters (Caps-Ag), which undergoes controllable 3D isomerism in cascaded responses to the tumor microenvironment, thereby leading to lysosome-targeting receptor (LTR)-mediated endocytosis. For effective modulation of the lysosomal-mitochondrial axis, the topology-dependent reactivity of AgNCs is strategically exploited, while the spatial confinement effect endowed by the 3D DNA nanoframework facilitates enhanced Ag+ release. Once internalized into lysosome, the 3D Caps-Ag is activated by the endogenously acidic and oxidative stimuli, which thus accelerates the release of Ag+ to disturb lysosomal membrane permeability (LMP) and the leakage of cathepsin B (CTSB) for attack mitochondrial membrane. The consequently activated cytochrome C (Cyt C)-mediated caspase-3 cascade reaction ultimately induces cell apoptosis. Both in vitro and in vivo studies demonstrate that the adaptive modulation achieved by Caps-Ag enhances tumor suppression, providing novel insights for advancing lysosomal-mitochondrial axis-induced therapeutics.