A DNA dual lock-and-key strategy for cell-subtype-specific siRNA delivery

TLDR

Efficient and precise siRNA delivery is essential for gene therapy, yet achieving cell‑specific targeting remains difficult due to nonspecific adsorption and off‑target effects. The authors design a dual lock‑and‑key system to enable cell‑subtype‑specific recognition and siRNA delivery. The system uses an oligonucleotide nano‑vehicle with a hairpin structure that serves as both a smart key and carrier; the hairpin is auto‑cleavable and activated on the target cell membrane by two sequential aptamer locks, allowing discrimination and precise delivery for efficient gene silencing. The strategy demonstrates precise siRNA delivery to specific target cells, achieving accurate gene silencing and opening avenues for RNAi in diagnosis and intervention.

Abstract

Abstract The efficient and precise delivery of siRNA to target cells is critical to successful gene therapy. While novel nanomaterials enhance delivery efficiency, it still remains challenging for precise gene delivery to overcome nonspecific adsorption and off-target effect. Here we design a dual lock-and-key system to perform cell-subtype-specific recognition and siRNA delivery. The siRNA is self-assembled in an oligonucleotide nano vehicle that is modified with a hairpin structure to act as both the ‘smart key’ and the delivery carrier. The auto-cleavable hairpin structure can be activated on site at target cell membrane by reacting with two aptamers as ‘dual locks’ sequentially, which leads to cell-subtype discrimination and precise siRNA delivery for high efficient gene silencing. The success of this strategy demonstrates the precise delivery of siRNA to specific target cells by controlling multiple parameters, thus paving the way for application of RNAi in accurate diagnosis and intervention.