{"doi":"10.1016/j.bioactmat.2025.04.017","title":"Human induced pluripotent stem cell derived nanovesicles for cardiomyocyte protection and proliferation","abstract":"It remains a significant challenge to reactivate the cell cycle activity of adult mammalian cardiomyocytes (CMs). This study created a hypo-immunogenic human induced pluripotent stem cell (hiPSC) line using clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 gene editing to knockout β2-microglobulin in hiPSCs ( B2MKO hiPSCs) for manufacturing nanovesicles ( B2MKO hiPSC-NVs). Approximately 9500 B2MKO hiPSC-NVs were produced from a single B2MKO hiPSC. Proteomic analyses indicated that, compared to B2MKO hiPSCs, the cargos of B2MKO hiPSC-NVs were enriched in spindle and chromosomal proteins, as well as proteins that regulate the cell cycle and scavenge reactive oxygen species (ROS). When administrated to hiPSCs derived CMs (hiPSC-CMs), B2MKO hiPSC-NVs reduced lactate dehydrogenase leakage and apoptosis in hypoxia-cultured hiPSC-CMs through activating the AKT pathway, protected hiPSC-CMs from H 2 O 2 -induced damage by ROS scavengers in the NV cargo, increased hiPSC-CM proliferation via the YAP pathway, and were hypoimmunogenic when co-cultured with human CD8 + T cells or delivered to mice. Furthermore, when B2MKO hiPSC-NVs or 0.9 % NaCl were intramyocardially injected into mice after cardiac ischemia/reperfusion injury, cardiac function and infarct size, assessed 4 weeks later, were significantly improved in the B2MKO hiPSC-NV group, with increased mouse CM survival and cell cycle activity. Thus, the proteins in the B2MKO hiPSC-NV cargos convergently activated the AKT pathway, scavenged ROS to protect CMs, and upregulated YAP signaling to induce CM cell cycle activity. Thus, B2MKO hiPSC-NVs hold great potential for cardiac protection and regeneration.","journal":"Bioactive Materials","year":2025,"id":518311,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.95,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1299950,"name":"Xiaoxiao Geng","orcid":null,"position":1,"is_corresponding":false},{"id":1385739,"name":"Qing You","orcid":"0000-0002-6573-270X","position":2,"is_corresponding":false},{"id":323005,"name":"Yu Zhang","orcid":"0000-0002-3315-9427","position":3,"is_corresponding":false},{"id":1385740,"name":"Fangfang Cao","orcid":"0009-0005-7414-1089","position":4,"is_corresponding":false},{"id":1386214,"name":"Gunaseelan Narayanan","orcid":null,"position":5,"is_corresponding":false},{"id":400653,"name":"Thanh Nguyen","orcid":"0000-0002-8440-1594","position":6,"is_corresponding":false},{"id":107398,"name":"Xiaoyuan Chen","orcid":"0000-0002-9622-0870","position":7,"is_corresponding":false},{"id":246346,"name":"Jianyi Zhang","orcid":"0000-0002-3955-6554","position":8,"is_corresponding":false},{"id":1275639,"name":"Lei Ye","orcid":"0000-0001-5039-6224","position":9,"is_corresponding":false},{"id":246343,"name":"Yuhua Wei","orcid":"0000-0003-0140-873X","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T02:49:09.679930Z","pmid":"40453695","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":[]}