Table 1.

Challenges of ncRNA delivery

Problem	Reason	Solution	References
Chemical instability characteristics of ncRNA	Physical and chemical properties Easily degraded by endogenous nuclease	Chemical or structural modification	Lee et al.; Sarett et al.; Whitehead et al.; Alexis et al.; Broderick et al.; Wilson et al.; Kooi et al.; Hacein-Bey-Abina69, 70, 71, 72, 73, 74, 75, 76
Extracellular and intracellular barriers	Irregular and heterogeneously high permeability of vascular tissue ncRNAs are susceptible to phagocytosis by late endosomes	Specifically targeting the vascular system and increasing the solubility of drugs Neutrally charged ionizable lipids can be used to induce lysosomal rupture, releasing ncRNAs	Wang et al.; Danquah et al.; Akhtar et al.; Semble et al.77, 78, 79, 80
The hurdle of immunogenicity	RNA interference, NF-κB activation, and pro-inflammatory cytokine production Type I interferon response	Third-generation modifications, such as PMOs	Winkle et al.; Barton et al.; Fabbri et al.; Cirak et al.; Sledz et al.17,81, 82, 83, 84)
Off-target effects	Induction of interferon response Partial complementarity of nucleic acid and unexpected targets	Specific targeted receptor ligand	Hanagata et al.; Jackson et al.; Juliano and Carver85, 86, 87)