Syringable\nMicrocapsules\nfor Sustained, Localized,\nand Controllable siRNA Delivery

The\nclinical use of small interfering RNA (siRNA) and\nantisense\noligonucleotides often requires invasive routes of administration,\nincluding intrathecal or intraocular injection. Additionally, these\ntreatments often necessitate repeated injections. While nanoparticle\nformulation and chemical modifications have extended siRNA therapeutic\ndurability, challenges persist, such as the side effects of bolus\ninjections with high toxicity and maximum exposure in the acute phase.\nWe present a microcapsule-based method to extend the activity of cholesterol-conjugated\nsiRNA locally. Using microfluidics, microcapsules with well-defined\nsize distribution and shell thickness are fabricated with poly(lactic-<i>co</i>-glycolic acid) (PLGA) with varying molecular weights\nand compositions. The microcapsules show a remarkably high drug encapsulation\nefficiency of nearly 100% and a high loading capacity (8900 μg\nsiRNA/1 mg polymer). Additionally, microcapsules with an average diameter\nof 40 μm show superior syringeability when tested with needles\nranging from gauge sizes of 27 to 32 G. This makes them suitable for\nvarious injection routes. Two sustained-release formulations were\nselected based on a 3-month in vitro release test. Subsequently, these\nformulations were injected subcutaneously into mice to verify their\nin vivo release profiles. The findings demonstrate that the microcapsules\neffectively shield the siRNAs from being cleared and enable them to\nbe released constantly over 3 months. In contrast, unencapsulated\nsiRNAs are rapidly cleared.