Spherical Nucleic Acids for Near-Infrared Light-Responsive Self-Delivery of Small-Interfering RNA and Antisense Oligonucleotide

Abstract

Herein, we developed a photolabile spherical nucleic acid (PSNA) for carrier-free and near-infrared (NIR) photocontrolled self-delivery of small-interfering RNA (siRNA) and antisense oligonucleotide (ASO). PSNA comprised a hydrophilic siRNA shell with a hydrophobic core containing a peptide nucleic acid-based ASO (pASO) and NIR photosensitizer (PS). The incorporation of a singlet oxygen (¹O₂)-cleavable linker between the siRNA and pASO allowed on-demand disassembly of PSNA in tumor cells once ¹O₂ was produced by the inner PS upon NIR light irradiation. The generated ¹O₂ could also concurrently promote lysosomal escape of the released siRNA and pASO to reach cytosolic targets. Both <i>in vitro</i> and <i>in vivo</i> results demonstrated that, under NIR light irradiation, PSNA could suppress hypoxia inducible factor-1α (HIF-1α) and B-cell lymphoma 2 (Bcl-2) for gene therapy (GT), which further combined photodynamic therapy (PDT) favored by the released PS to inhibit tumor cell growth. Given its carrier-free, NIR-sensitive, designable, and biocompatible merits, PSNA represents a promising self-delivery nanoplatform for cancer therapy.