{"doi":"10.1016/j.omtn.2021.03.007","title":"Stoichiometry of multi-specific immune checkpoint RNA Abs for T cell activation and tumor inhibition using ultra-stable RNA nanoparticles","abstract":"Immunotherapy has become a revolutionary subject in cancer therapy during the past few years. Immune checkpoint-targeting antibodies (Abs) could boost anticancer immune responses. However, certain protein-based immunotherapies revealed side effects and unfavorable biodistribution, so effective non-protein options with lower side effects are highly sought after. RNA's ability to form various three-dimensional configurations allows for the creation of a variety of ligands to bind different cell receptors. The rubber-like properties of RNA nanoparticles (NPs) allow for swift lodging to cancer vasculature with little accumulation in vital organs, resulting in a favorable pharmacokinetic/pharmacodynamic (PK/PD) profile and safe pharmacological parameters. Multi-specific drugs are expected to be the fourth wave of biopharmaceutical innovation. Herein, we report the development of multi-specific Ab-like RNA NPs carrying multiple ligands for immunotherapy. The stoichiometries and stereo conformations of the checkpoint-activating RNA NPs were optimized for T cell activation. When compared to mono- and bi-specific RNA NPs, the tri-specific Ab-like RNA NPs bound to the trimeric T cell receptor with the highest efficiency, showed the optimal T cell activation, and promoted the strongest anti-tumor function of immune cells. Animal trials demonstrated that the tri-specific RNA NPs inhibited cancer growth. This Ab-like RNA NP platform represents an alternative to protein Abs for tumor immunotherapy.","journal":"Molecular Therapy — Nucleic Acids","year":2021,"id":198307,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9511,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":772991,"name":"Long Zhang","orcid":"0000-0002-6811-0439","position":1,"is_corresponding":false},{"id":493715,"name":"Xue‐Feng Bai","orcid":"0000-0001-9476-8376","position":2,"is_corresponding":false},{"id":253516,"name":"Jianhua Yu","orcid":"0000-0002-0326-3223","position":3,"is_corresponding":false},{"id":255310,"name":"Peixuan Guo","orcid":"0000-0001-5706-2833","position":4,"is_corresponding":false},{"id":420819,"name":"Dan Shu","orcid":"0000-0002-0267-1102","position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":null,"created_at":"2026-07-18T23:50:27.616568Z","pmid":"33868786","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}