Designed trimer-mimetic TNF superfamily ligands on self-assembling nanocages

Biomaterials
Minwoo KihIn-San Kim

Abstract

Presentation of an endogenous bioactive ligand in its native form is a key factor in controlling and determining its bioactivity, stability, and therapeutic efficacy. In this study, we developed a novel strategy for presenting trimeric ligands on nanocages by designing, optimizing and testing based on the rational design, high-resolution structural analysis and agonistic activity assays in vitro and in vivo. We successfully designed a nanocage that presents the TNF superfamily member, TRAIL (TNF-related apoptosis-inducing ligand) in its native-like trimeric structure. The native structure of TRAIL complexes was mimicked on the resulting trimeric TRAIL-presenting nanocages (TTPNs) by inserting sufficient spacing, determined from three-dimensional structural models, to provide optimal access to the corresponding receptors. The efficacy of TTPNs as an anti-tumor agent was confirmed in preclinical studies, which revealed up to 330-fold increased affinity, 62.5-fold enhanced apoptotic activity, and improved pharmacokinetic characteristics and stability compared with the monomeric form of TRAIL (mTRAIL). In this latter context, TTPNs exhibited greater than 90% stability over 1 mo, whereas ∼50% of mTRAIL aggregated within 2 d. Consist...Continue Reading

Citations

Jan 16, 2021·Journal of Controlled Release : Official Journal of the Controlled Release Society·Hyeonwoo JeEun Jung Lee
Jan 13, 2021·Journal of Controlled Release : Official Journal of the Controlled Release Society·Minsu KwonIn-San Kim
Apr 2, 2021·Journal of Controlled Release : Official Journal of the Controlled Release Society·Gi Beom KimIn-San Kim

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