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

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 (O-1(2))-cleavable linker between the siRNA and pASO allowed on-demand disassembly of PSNA in tumor cells once O-1(2) was produced by the inner PS upon NIR light irradiation. The generated O-1(2) could also concurrently promote lysosomal escape of the released siRNA and pASO to reach cytosolic targets. Both in vitro and in vivo results demonstrated that, under NIR light irradiation, PSNA could suppress hypoxia inducible factor-1 alpha (HIF-1 alpha) 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.