Background/Objectives: Intrathecal drug delivery is essential for treating CNS disorders, but the safety of commonly used excipients such as citric acid/sodium citrate (SC) remains unclear. This study aims to systematically evaluate the potential neuropharmacological effects of repeated intrathecal SC administration. Methods: Multimodal approaches were applied across murine and lagomorph models. Doses ranged from 1.833–14.664 μg/g in mice and 0.104–3.290 mg/rabbit. Behavioral, neurophysiological, and fiber photometry analyses were conducted to assess sensorimotor function, cortical activity, and calcium dynamics. Results: SC induced dose-dependent sensorimotor deficits, including hypolocomotion (45.7% reduced distance, p < 0.001) and impaired coordination (latency reduction 48.3–64.1%, p < 0.001). Mortality increased with dosage and repeated exposure. Neurophysiological data revealed biphasic cortical modulation: acute c-Fos suppression followed by delayed hyperactivity. Fiber photometry confirmed calcium chelation-mediated attenuation and subsequent potentiation of Ca²⁺ signals. Rabbits exhibited similar neurological symptoms, correlating with transient CSF calcium/magnesium depletion, though no structural neural damage was observed. Conclusions: These results provide the first comprehensive evidence that SC buffers can significantly disrupt neuronal calcium homeostasis and induce functional impairments upon intrathecal delivery. The findings emphasize the need for reassessing excipient safety in CNS-targeted formulations.

Background and Objective: Hyaluronic acid (HA) solutions possess unique shear-thinning properties critical for their material processability in biomedical applications. However, existing simulations mainly focus on static hydration structures, lacking mesoscopic insights into chain conformational dynamics and topological disentanglement under steady shear. This study aims to systematically elucidate the deep mesoscopic physical mechanism underlying the shear-thinning behavior of HA solutions.,Methods: Dissipative particle dynamics (DPD) was utilized to construct coarse-grained models of HA with low, medium, and high molecular weights (200k, 1.2M, and 1.8M). Systematic simulations were performed to quantitatively evaluate adjacent bond length evolution, spatial velocity profiles, radius of gyration (Rg ), and mean square displacement (MSD) under steady shear flow.,Results: The results indicate that excessive shear rates (≥1 ps⁻¹） trigger non-physical bond stretching, defining the physical validity regime for simulation conditions. Under steady intense shear, high-molecular-weight systems exhibit non-linear, S-shaped velocity profiles, signifying a pronounced local shear-banding response and spatial heterogeneity. Driven by shear accumulation, the flexible polymer chains stretch intensely along the flow direction, with Rg monotonically increasing up to 20-fold for the longest chains, thereby leading to the progressive deconstruction of the physical entanglement network. Furthermore, MSD analysis confirms a surge in the self-diffusion coefficient by over four orders of magnitude, marking a sharp kinetic transition from localized confined diffusion to fast directional slipping. By the Stokes-Einstein relation, this exponential leap in mesoscopic diffusivity directly maps to the abrupt decline in macroscopic dynamic viscosity.,Conclusions: This work establishes a coherent mesoscopic picture of "shear flow - chain orientation/extension - entanglement deconstruction - slip dissipation transition". It clarifies the dynamical essence of shear thinning, successfully complementing the atomistic hydrogen-bond disruption mechanism and providing a solid multiscale foundation for HA fluid engineering.