The discovery of microRNAs (miRNAs) in 1993 has challenged the dogma of gene expression regulation. MiRNAs affect most of cellular processes from metabolism, through cell proliferation and differentiation, to cell death. In cancer, deregulated miRNA expression leads to tumor development and progression by promoting acquisition of cancer hallmark traits. The multi-target action of miRNAs, which enable regulation of entire signaling networks, makes them attractive tools for the development of anti-cancer therapies. Hence, supplementing downregulated miRNA by synthetic oligonucleotides or silencing overexpressed miRNAs through artificial antagonists became a common strategy in cancer research. However, the ultimate success of miRNA therapeutics will depend on solving pharmacokinetic and targeted delivery issues. The development of a number of nanocarrier-based platforms holds significant promises to enhance the cell specific controlled delivery and safety profile of miRNA-based therapies. In this review, we provide among the most comprehensive assessments to date of promising nanomedicine platforms that have been tested preclinically, pertaining to the treatment of selected solid tumors including lung, liver, breast, and glioblastoma tumors as well as endocrine malignancies. The future challenges and potential applications in clinical oncology are discussed.

Gene fusions generated by chromosomal rearrangements function as oncogenic drivers in human cancers. We previously showed that EWSR1-ETS oncofusions of Ewing sarcoma (EwS) directly induce surface expression of IL1 receptor accessory protein (IL1RAP), which along with limited expression in healthy tissues except placenta nominate IL1RAP as a promising EwS immunotherapy target. We therefore engineered antibody-drug conjugates (ADCs) with different cytotoxic payloads to target IL1RAP. ADCs potently blocked tumor growth and induced durable regression of EwS xenografts in mice, and diminished metastatic dissemination in vivo. Moreover, we show that other oncofusions also induce IL1RAP expression in diverse cancers, including NPM-ALK in anaplastic large cell lymphoma (ALCL), and ETV6-NTRK3 in multiple tumor types. IL1RAP expression rendered these malignancies similarly vulnerable to IL1RAP-targeting ADCs, which effectively blocked growth of ALCL xenografts and syngeneic ETV6-NTRK3+ sarcomas. Lack of detectable normal tissue toxicity, including in non-human primates, support the further clinical translation of IL1RAP-targeting ADCs.

Supplementary Figure S8. 7D12-PBD mitigates EwS metastasis in vivo with high potency.

Supplementary Figure S7. In vivo ADC biodistribution analysis by near-infrared (NIR) imaging.

Supplementary Figure S5. Cross-species reactivity of the 7D12 binder to human and murine IL1RAP enables evaluation of potential on-target and off-target toxicities in mice.

Supplementary Figure S4. Engineering of a humanized IgG1 IL1RAP-targeting ADC for immunotherapy.