Simulation-Guided Design and Synthesis of Functionalized Lactose-Crosslinked Degradable Molecularly Imprinted Polymer Nanoparticles for Sialic Acid Recognition.

Aberrant cell-surface sialylation is widely associated with cancer progression and provides an accessible molecular feature for biosensing and targeted delivery. However, engineering molecularly imprinted polymer nanoparticles (nanoMIPs) that combine selective sialic acid (SA) recognition with controlled degradability and cytocompatibility remains challenging. In this study, a simulation-guided strategy was used to develop hydrolytically degradable SA-imprinted nanoMIPs incorporating a functionalized lactose-based crosslinker with cleavable ester linkages. Molecular docking and quantum-chemical calculations identified N-isopropylacrylamide (NIPAM), acrylamide (AAm), and N-hydroxyethyl acrylamide (HEAA) as complementary functional monomers and established an optimized SA:NIPAM:AAm:HEAA molar ratio of 1:1:2:1. The resulting nanoMIPs were spherical and nanoscale and exhibited pH-dependent hydrolytic mass loss that was more pronounced under mildly acidic conditions than at physiological pH. Compared with non-imprinted nanoparticles, the nanoMIPs displayed substantially enhanced SA binding, with a maximum binding capacity of 89.38 μmol g-1 and an imprinting factor of approximately 4.2, together with preferential recognition of SA over the selected competing molecules. MTT assays using MCF-7, HeLa, and HaCaT cells showed cell viability above 80% after 24 h exposure to 500 μg mL-1, indicating favorable short-term cytocompatibility. By integrating computationally optimized, multicomponent SA recognition with a carbohydrate-derived, hydrolytically degradable crosslinking strategy, this work addresses the coupled requirements of binding-site fidelity and material degradability within a single nanoMIP platform. These findings establish a materials-level foundation for future SA-directed biosensing and targeted delivery systems in cancer-relevant applications.