Bridging the gap: using organ-on-a-chip technology to evaluate nanoparticle enzyme replacement therapy for lysosomal storage diseases.

Introduction: Development for lysosomal storage diseases (LSDs) remains challenging because enzyme replacement therapy (ERT) exhibits limited tissue distribution and high immunogenicity. Although nanoparticle encapsulation can improve enzyme delivery, preclinical models inadequately predict human responses. Conventional in vitro assays lack continuous flow and physiological shear stress, potentially promoting artificial nanoparticle accumulation, whereas animal models often fail to reproduce human physiology. Organ-on-a-Chip (OoC) addresses these limitations by recreating in vivo conditions within microfluidic in vitro platforms, thereby supporting realistic cellular metabolism, growth, and intercellular communication. This review examines the potential of OoC platforms to advance nanoparticle-based ERT for LSDs.

Areas covered: Engineered microchannels generate dynamic flow and shear stress, enabling assessment of nanoparticle-cell interactions, intracellular trafficking, tissue-barrier crossing, and other critical pharmacological parameters under physiopathologically relevant conditions. Literature published over the past twenty years was identified through PubMed, Scopus, and Web of Science. Nanoparticle functionalization strategies for targeting tissues affected by LSDs and their incorporation into OoC models are also discussed.

Expert opinion: Despite major challenges, particularly the lack of methodological standardization, integrating OoC systems, patient-derived cells, and nanoparticle-based ERT could transform preclinical research, support personalized medicine, accelerate clinical translation, and help address persistent unmet therapeutic needs among patients with LSDs.