Figure 1 The review article published in Drug Discovery Today.

This article introduces the development landscape of ONTs, including major therapeutic modalities and their unique mechanisms of action, while addressing the translational challenges associated with species differences in conventional nonclinical models. Human-relevant NAMs, including organoids and organ-on-a-chip platforms, represent emerging approaches to improve the evaluation of target engagement, RNA modulation, drug delivery, and safety profiles.

The biological basis and application strategies of human-relevant models for liver-targeted ONTs are described, highlighting the capabilities of liver organoids and liver-on-a-chip platforms in recapitulating human-specific hepatic uptake, intracellular trafficking, exposure dynamics, and pharmacological responses. These models provide valuable insights into liver-targeted delivery mechanisms and potential safety liabilities.

Beyond the liver, organoid platforms have been applied across multiple tissues, including the retina, brain, heart, intestine, kidney, and tumor models. By preserving human cellular characteristics, tissue architecture, and disease-relevant phenotypes, these models enable mechanistic and functional studies that cannot be fully captured by traditional animal systems.

Organ-on-a-chip platforms further reproduce dynamic physiological environments, allowing investigation of tissue transport, cellular interactions, exposure responses, and functional outcomes.

Finally, regulatory considerations, COU, and future integration strategies are discussed to support the broader application of NAMs in ONT development.

Figure 2 Representative organ-on-a-chip platforms in ONT development. Organ-on-a-chip platforms used in the nonclinical evaluation of ONTs, supporting the investigation of cellular uptake, intracellular distribution, and pharmacological responses under controlled in vitro conditions.

Figure 3 Organoids in ONT development. Representative organoid systems and their applications in evaluating target engagement, RNA modulation, and cellular responses in tissue-relevant 3D cultures.