Microfluidic-Driven Assembly of RNA Nanocomplexes: Design, Process Control and Translational Perspectives in Oncology

RNA-based therapeutics are becoming increasingly important in oncology, particularly following the rapid development of mRNA technologies during the COVID-19 pandemic, but their success strongly depends on how efficiently they can be delivered to target cells. Microfluidic technologies have redefined the design and manufacturing of RNA-based nanocomplexes, as they enable precise control over physicochemical features that are critical for clinical translation in oncology. This review examines recent developments in microfluidic-assisted synthesis of RNA nanocarriers, with a focus on cancer applications. Through a detailed analysis of material systems, device architectures, and formulation strategies, we explore how laminar flow environments enable reproducible encapsulation, tunable particle size, and improved payload stability. We examine the microfluidic assembly of lipid nanoparticles and polymeric carriers for RNA delivery, highlighting strategies to enhance durability, bioavailability, and cellular uptake. Advancements in process optimization, including flow parameter refinement and inline monitoring, are discussed alongside the influence of device geometries on mixing dynamics and nucleation. Beyond formulation, we explore the integration of microfluidics with tumor-on-chip platforms to evaluate transport, penetration, and therapeutic response in physiologically relevant cancer models. By connecting technological innovation with preclinical application, this work outlines the trajectory toward next-generation, personalized RNA nanomedicines enabled by microfluidic precision.