Syringable Microcapsules for Sustained, Localized, and Controllable siRNA Delivery

Abstract

The clinical use of small interfering RNA (siRNA) and antisense oligonucleotides often requires invasive routes of administration, including intrathecal or intraocular injection. Additionally, these treatments often necessitate repeated injections. While nanoparticle formulation and chemical modifications have extended siRNA therapeutic durability, challenges persist, such as the side effects of bolus injections with high toxicity and maximum exposure in the acute phase. We present a microcapsule-based method to extend the activity of cholesterol-conjugated siRNA locally. Using microfluidics, microcapsules with well-defined size distribution and shell thickness are fabricated with poly(lactic-co-glycolic acid) (PLGA) with varying molecular weights and compositions. The microcapsules show a remarkably high drug encapsulation efficiency of nearly 100% and a high loading capacity (8900 μg siRNA/1 mg polymer). Additionally, microcapsules with an average diameter of 40 μm show superior syringeability when tested with needles ranging from gauge sizes of 27 to 32 G. This makes them suitable for various injection routes. Two sustained-release formulations were selected based on a 3-month in vitro release test. Subsequently, these formulations were injected subcutaneously into mice to verify their in vivo release profiles. The findings demonstrate that the microcapsules effectively shield the siRNAs from being cleared and enable them to be released constantly over 3 months. In contrast, unencapsulated siRNAs are rapidly cleared.