IGF1R-Targeted Delivery of a Bridged Nucleic Acid Oligonucleotide-Peptide Conjugate for MicroRNA 21 Inhibition in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC), defined by the absence of ER, PR, and Her2, impacts over 46,000 U.S. women annually, disproportionately affecting minority ethnic groups and individuals with BRCA1 mutations. Despite advancements such as PARP inhibitors, TNBC remains highly aggressive, with frequent recurrences and a 50% mortality rate within four years, underscoring the urgent need for more effective targeted therapies. MicroRNAs (miRNAs) represent a novel therapeutic approach. In TNBC, overexpressed miR-21 drives tumor progression, immune evasion, treatment resistance, and metastasis. Targeted miR-21 inhibition could curb these effects while minimizing harm to normal cells. We developed a peptide-conjugated miR-21 inhibitor targeting TNBC cells via the overexpressed IGF1 receptor (IGF1R), associated with poor prognosis. Using aminomethyl-bridged nucleic acid (BNA) chemistry, a serum-stable, low-toxicity anti-miR-21 RNA analog was created and tested for its effects on TNBC cell proliferation, apoptosis, tumor suppressor expression, and immune checkpoint regulation. Conjugation to an IGF1 peptide analog improved delivery, demonstrating tumor-specific biodistribution, efficacy, and safety in TNBC-bearing mice. The miR-21 inhibitor-peptide conjugate reduced proliferation, induced apoptosis, elevated tumor suppressors, and suppressed immune checkpoints in TNBC cell lines. In vivo, it targeted tumors, halted growth, and showed no liver or kidney toxicity, supporting its potential as a targeted, low-toxicity TNBC therapy.