Nanobody-guided targeted delivery of microRNA via nucleic acid nanogel to inhibit the tumor growth

MicroRNAs (miRNAs) play crucial roles in maintaining normal physiological processes by regulating gene expression network and thus the tumor-suppressive miRNA has emerged as a promising antitumor agent for cancer treatment. However, targeted delivery of miRNA remains a challenge owing to its intrinsic macromolecular and negatively-charged features. Herein, we first employ the miRNA as crosslinker to construct a nucleic acid nanogel, in which miRNA is embedded and protected inside the three-dimensional (3D) nanostructure. Thereafter, nanobody (Nb) conjugated DNA (Nb-DNA) strands are further loaded on nanogel surface through nucleic acid hybridization, to form a Nb-functionalized nanogel (Nb-nanogel) for tumor-targeted miRNA delivery and antitumor treatment. Both in vitro and in vivo experiments show that nanogel equipped with Nb targeting moieties can greatly promote the miRNA accumulation at the tumor site and cellular uptake efficiency, resulting in significant improvement of the miRNA-mediated antitumor efficacy. This research provides a new approach for targeted miRNA delivery and may pave a new avenue to realize efficient miRNA replacement therapy for cancer treatment.