Compartmentalized co-delivery of CD73 (ecto-5'-nucleotidase) mRNA and rotenone using pH/ROS dual-responsive microgels for neuroinflammation therapy.

Neuroinflammation remains challenging to treat due to its complex pathophysiology. Combining anti-inflammatory and antioxidant actions represents a key strategy for efficient therapy. Herein, we developed a reactive oxygen species (ROS)/pH-sensitive microgel drug delivery system based on micelles composed of PDPA75-PEI42-PEG45 and PDPA75-PEI42, enabling compartmentalized co-loading of two drugs. The PEI layer of the micelles was cross-linked using a ROS-cleavable thioketal (TK) group, while the connection between PEG45 and PEI42 is designed to be acid-cleavable, allowing PEI exposure to facilitate cell transfection. This microgel, termed MicelleGEL, achieved controlled and independent release of two compartmentalized drugs under high ROS levels and mild acidity conditions. In vitro studies confirmed that the MicelleGEL efficiently delivered CD73 (ecto-5'-nucleotidase) mRNA into BV2 cells, leading to CD73 protein expression, which exerted anti-inflammatory effects and regulated the M1-to-M2 polarization. Meanwhile, MicelleGEL-mediated delivery of rotenone effectively inhibited ROS production induced by the reverse electron transfer (RET) pathway. Furthermore, the compartmentalized co-loading design facilitated effective intracellular delivery of both CD73 mRNA and rotenone, promoting synergistic therapeutic effects against oxidative stress. The microgel platform thus offers a promising strategy for the precise and efficient treatment of neuroinflammation and opens a new avenue for co-delivery with controlled release.