Dynamic polymeric nanomedicines for nucleic acid delivery

Nucleic acid therapeutics, including antisense oligonucleotides (ASOs), small interfering RNA (siRNA), and messenger RNA (mRNA), show great promise in the treatment of intractable diseases, such as genetic disorders and cancers. However, their clinical applications are currently limited due to poor biodistribution, which is hindered mainly by dynamic biological barriers, including circulation shear, tissue penetration, and inefficient cellular uptake. Enhancing the dynamic behaviour of nanomedicines has emerged as a promising strategy to overcome these challenges. In our laboratory, we have developed an ultra-small dynamic nanomedicine termed the unit polyion complex (uPIC) by assembling a single molecular oligonucleotide with PEGylated block cationic polymers. This dynamic intermediate complex, formed before core–shell micelle stabilisation, exhibits structural flexibility that enables it to adapt to physiological environments and enhance delivery performance. In this presentation, we will highlight recent advances in using uPIC for the tunable delivery of oligonucleotides. First, we will describe how dynamic enhancement can be utilized to enhance the delivery of ASOs via systemic administration, thereby achieving functional gene silencing in orthotopic glioblastoma. We will then demonstrate how further dynamic tuning enables efficient local delivery to tumor-draining lymph nodes, thereby rejuvenating CD8⁺ T cell–mediated immune responses to inhibit breast cancer recurrence and metastasis.

Kanjiro Miyata, PhD – Professor, Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo