Table 1.

Unique features of tRNA medicines as compared with other RNA modalities

Therapeutic mechanism & application	siRNA	mRNA	tRNA	tRF
Mechanism of action	Targets specific RNAs for degradation	Provides a functional mRNA	Functionally corrects/recodes endogenous mutation	Generally regulates biological pathways
Control of target gene expression	Fully leverages endogenous control pathways	Encodes in the exogenous mRNA	Fully leverages endogenous control pathways	Fully leverages endogenous control pathways
Addressable patient population for each medicine	Each disease target requires full development	Each disease target requires full development	Addresses entire class of mutations independent of nature of gene/protein	Depends on biological application
Specifications	siRNA	mRNA	tRNA	tRF
Drug substance/RNA optimization	Full scope of combinatorial sequence and modification exploration optimizes drug properties∗	Primary sequence and higher order structure design restricts encoded protein sequence and translationally competent modifications	Full scope of combinatorial sequence and modification exploration optimizes drug properties	Full scope of combinatorial sequence and modification exploration optimizes drug properties∗
Size	Small (<25 nucleotides for single strand)	Hundreds to thousands of nucleotides	Relatively small (<100 nucleotides)	Small (<40 nucleotides)
Synthesis	Chemical	Enzymatic	Chemical Enzymatic	Chemical Enzymatic
Delivery	Nanoparticle Viral Conjugation	Nanoparticle Viral	Nanoparticle Viral Conjugation	Nanoparticle Viral Conjugation

A comparison of the molecular mechanisms of action, addressable patient population, and modality design and delivery parameters across RNA modalities, namely siRNA, mRNA, tRNA, and tRFs.

^∗With restrictions based on complementarity to target.