Kih, Minwoo Lee, Eun Jung Lee, Na Kyeong Kim, Yoon Kyoung Lee, Kyung Eun Jeong, Cherlhyun Yang, Yoosoo Kim, Dong-Hwee Kim, In-San 2024-01-19T21:33:49Z 2024-01-19T21:33:49Z 2021-09-05 2018-10 0142-9612 https://pubs.kist.re.kr/handle/201004/120839 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 TrPNs 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, TrPNs exhibited greater than 90% stability over 1 mo, whereas similar to 50% of mTRAIL aggregated within 2 d. Consistent with their enhanced stability and ultra-high affinity for the TRAIL receptor, TrPNs effectively induced apoptosis of tumor cells in vivo, leading to effective inhibition of tumor growth. Although TRAIL was used here as a proof-of-concept, all members of the TNF superfamily share the TNF homology domain (THD) and have similar distances between ecto-domain C-termini. Thus, other TNF superfamily ligands could be genetically substituted for the TRAIL ligand on the surface of this bio-mimetic delivery platform. (C) 2018 Elsevier Ltd. All rights reserved. English ELSEVIER SCI LTD APOPTOSIS-INDUCING LIGAND TRAIL-INDUCED APOPTOSIS CAGE NANOPARTICLES CANCER-THERAPY RECEPTOR FERRITIN APO2L/TRAIL PHARMACOKINETICS COMBINATION EFFICACY Designed trimer-mimetic TNF superfamily ligands on self-assembling nanocages Article 10.1016/j.biomaterials.2018.07.009 1 BIOMATERIALS, v.180, pp.67 - 77 BIOMATERIALS 180 67 77 scie scopus 000442056500006 2-s2.0-85053184687 Engineering, Biomedical Materials Science, Biomaterials Engineering Materials Science Article APOPTOSIS-INDUCING LIGAND TRAIL-INDUCED APOPTOSIS CAGE NANOPARTICLES CANCER-THERAPY RECEPTOR FERRITIN APO2L/TRAIL PHARMACOKINETICS COMBINATION EFFICACY Nanocages Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) Biomimetic delivery platform Trimeric structure Stability