Year: 2026
Type: article
Abstract: Transcription factors (TFs) are often considered undruggable due to their structural complexity. mRNA technologies can overcome this therapeutic limitation by enabling dynamic protein replacement therapies. Here, we explore the TF activity of LCOR (Ligand-dependent corepressor), which suppresses tumor growth, at least in part by inducing the antigen presentation machinery (APM) in tumor cells and constraining cellular plasticity. These effects facilitate tumor immune recognition and immune-mediated tumor eradication. We used poly β-(amino esters) (pBAE) nanoparticles (NPs) for local delivery of Lcor mRNA in multiple breast cancer models. pBAE-NPs efficiently encapsulate mRNA and facilitate cellular uptake, achieving optimal endosomal escape, resulting in high transfection efficiency in vitro and in vivo, restoring LCOR function in tumor cells and engaging their APM. In preclinical models, intratumoral delivery of Lcor mRNA reduced tumor growth. Importantly, the combination of Lcor mRNA-loaded RH-pBAE-NPs with anti-PDL1 or anti-CTLA4 immunotherapies eradicated most of the tumors in our preclinical TNBC model. Overall, our nanotherapeutic strategy emerges as an innovative TF-replacement therapy in a lock-in/wipe-out fashion, leveraging the immunogenic effects of LCOR to eradicate breast cancer tumors when combined with immunotherapy.
Source: Molecular Oncology
Institutions: Hospital Del Mar, Institut Químic de Sarrià
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,300
Funders: “la Caixa” Foundation, Ministerio de Ciencia, Innovación y Universidades, European Commission, Fundación Científica Asociación Española Contra el Cáncer, Generalitat de Catalunya, Institució Catalana de Recerca i Estudis Avançats, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, European Regional Development Fund, Agencia Estatal de Investigación
Awards: G1105844351, G1151018826, G1271571328, G1272900390, G1537488600, G1708238744, G1816490682, G1941306306, G2064873908, G2462415295, G2661222962, G288263039, Nanoformulaciones, seguridad e inmunidad de la presentación mediada de antígenos tumorales en la inmunoterapia., G3005324705, G410571670, G451917667, G4779471942, G4931825208, G5289244179, G5635532810, G5852091828, G5967599077, Vacunas de mRNA innovadoras contra el NSCLC: Diseñando una plataforma de nanopartículas poliméricas dirigidas para terapia personalizada, G717256432, G7466406081, G7805626310, G7863371703, G8497050386, G8577119683, G8733500679, G9001302168, G9001302494, G9001302581, G9001303131, G9001303264
OpenAlex ID: W7221935910