Mechanical Flexibility Enables DNA Origami to Overcome Steric Confinement in Mucus

ABSTRACT Size exclusion within biological hydrogels imposes a fundamental constraint on the design of nanocarriers, limiting the transport of cargo‐loaded and structurally complex materials through mucus barriers. While surface passivation strategies are commonly used to improve compatibility, they do not address steric limitations imposed by the polymer network. Here, we introduce mechanical flexibility as an independent materials design parameter to expand the functional transport window of nanocarriers in mucus. Using programmable DNA origami to decouple flexibility from size and surface chemistry, we show that increased structural compliance enhances transport under steric confinement by facilitating passage through confined network pores. When surface‐driven aggregation dominates, passivation is required to restore transport, after which flexibility provides additional gains. Together, these results establish mechanical flexibility as a general materials design strategy for improving transport under size‐constrained conditions, with implications for nanocarrier engineering across biological barriers.