Hydrogel-forming Microneedles for Multi-drug and Phytochemical Co-delivery: Translational Opportunities in Autoimmune...

Autoimmune diseases such as rheumatoid arthritis represent major clinical challenges due to the complexity of immune system dysfunction and the limitations of current treatment strategies. Combination therapies involving JAK inhibitors, methotrexate, and natural compounds such as quercetin can target multiple disease pathways and improve therapeutic outcomes. Previous studies have shown that the concurrent administration of multiple medications may result in reduced patient adherence, systemic adverse effects, and suboptimal tissue targeting. Hydrogel-Forming Microneedles (HFMNs) enable controlled transdermal drug delivery, offering a minimally invasive approach that may improve patient acceptability and facilitate the administration of multiple therapeutic agents. This review examines the design principles of HFMNs, including polymer selection, crosslinking strategies, swelling behavior, and drug-loading approaches, and compares them with other microneedle platforms. Recent advances have focused on the co-encapsulation of multiple therapeutic agents, including synthetic drugs, Disease-Modifying Antirheumatic Drugs (DMARDs), and phytochemicals, enabling their controlled and sequential release for enhanced therapeutic efficacy. Recent studies have investigated drug-material interactions, in vitro and in vivo release profiles, and the synergistic effects of co-delivered therapeutic agents. Particular emphasis is placed on the application of combination therapy in rheumatoid arthritis through modulation of the JAK/STAT, NF-κB, and oxidative stress pathways, while HFMN-mediated delivery may improve therapeutic outcomes and reduce systemic adverse effects. Ongoing studies have evaluated the development of these systems, including their mechanical strength, transdermal penetration performance, and therapeutic efficacy in animal models of inflammatory joint disease using relevant biomarker analyses. The review also discusses regulatory considerations, including scale-up manufacturing and sterilization, and highlights future directions involving smart hydrogels and integrated diagnostic technologies to facilitate clinical translation. HFMNs provide a versatile platform for advancing combination therapies for autoimmune and inflammatory diseases. This platform has the potential to improve tissue targeting, patient adherence, and therapeutic outcomes.