Synergistic Combination of Bioengineered MicroRNA and Chemotherapy Across High-Risk Neuroblastoma Subtypes

Despite intensive treatment, high-risk neuroblastoma (HRNB) remains a leading cause of cancer-related mortality in children. Current treatment paradigms include multimodal systemic treatments and multi-agent chemotherapy, which is limited by substantial acute and long-term toxicities. Platinum-based chemotherapy is a cornerstone of this treatment but is fraught with side effects and stands to benefit from dose reduction strategies. MicroRNA (miR)-based therapeutics represent an attractive strategy to simultaneously moderate multiple oncogenic pathways, providing a potential avenue to enhance the efficacy of current treatment regimens. However, the development of miR therapeutics has largely relied on chemically synthesized ones, which are limited by issues of inconsistency and poor in vivo stability. Biologically produced, tRNA/pre-miR containing bioengineered miRs (bioRNAs) address these limitations. We investigated the therapeutic potential of bioRNA encoding miR-124 and miR-34a across molecularly distinct HRNB models and evaluated their ability to enhance cisplatin efficacy. Both bioRNAs significantly suppressed neuroblastoma cell viability in vitro, with proteomic analyses demonstrating preferential induction of neuronal differentiation by miR-124 and apoptotic signaling by miR-34a. Combining bioRNA with cisplatin produced robust synergy across multiple HRNB lines, enhancing apoptosis while simultaneously promoting differentiation-associated phenotypes. In vivo, both bioRNAs suppressed tumor growth as monotherapies, while combination with low-dose cisplatin produced the strongest responses across multiple xenograft models with different HRNB subtypes. Notably, low-dose cisplatin combined with bioRNA therapy frequently achieved tumor control comparable to, or greater than, that observed with high-dose cisplatin monotherapy while maintaining favorable tolerability. These findings establish bioRNAs as potent cisplatin sensitizers and support bioRNA-based combination therapy as a strategy for improving HRNB treatment while reducing chemotherapy-associated toxicity in children.