Inflammatory signals both drive damage and participate in repair, so interventions need to target the right pathogenic mediators and hit the right timing. DNA enzymes can cut RNA according to transcripts, but controlling the potent sequences and catalytic start timing is tricky. The study used machine learning to screen high-activity DNA enzymes targeting TNF-α and summarized design principles based on RNA accessibility and RNA–DNA interaction energetics; then they loaded the optimized DNA enzymes into upconversion nanoparticles conjugated with DNA nanocages, using light-cleavable linkers to achieve near-infrared-triggered release and spatiotemporal control of silencing.

This construct showed anti-inflammatory activity in macrophages, and after microneedle delivery, combined with Etanercept, it was effective in TNF-related inflammatory skin models. When further applied to diabetic bone regeneration, delayed activation preserved early beneficial inflammation and promoted subsequent resolution via enhanced efferocytosis, accelerating bone repair. This moves DNA enzyme interventions from indiscriminate suppression toward stage-specific immune modulation, forming a machine-learning-guided, light-activated DNA enzyme nanocage strategy.

Reference:
DOI:10.1002/adfm.78518

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