Liposomal design and shear shielding of colloidal matrices control drug release

The drug release of liposomes is strongly modulated by mechanical stress, yet the interplay between carrier properties and the surrounding colloidal environment remains difficult to resolve experimentally due to the challenge of preserving shear conditions and carrier microenvironment during measurement. Here, we address this limitation using the Dispersion Releaser, a USP-referenced dialysis-based platform that enables in situ quantification of release under continuous shear. Computational fluid dynamics (CFD) simulations were used to map flow regimes across 25-100 rotations per minute (RPM), informing the selection of 25 RPM (low shear) and 75 RPM (high shear) for subsequent experiments. Two berberine-loaded liposomal formulations with distinct drug-dipalmitoylphosphatidylglycerol electrostatic interaction strengths showed significantly different release profiles under laminar flow, low-shear environment (f2 = 40.32) but converged under high shear (f2 = 68.31), and closely approached the permeation of free berberine, indicating that drug-membrane affinity governs release under mild shear but is overridden at higher mechanical stress. To investigate the role of the colloidal microenvironment, hydroxypropyl methylcellulose was introduced as an inert, non-permeable, shear-thinning matrix at concentrations of 1.5% and 2.5%. A dedicated permeation normalization separated the diffusional contribution of each matrix from carrier-mediated release. After normalization, the 2.5% matrix reduced cumulative release from ∼ 87% to ∼ 54% at 25 RPM, while the release modulation by the 1.5% was lost at 75 RPM. Notably, CFD revealed that both matrices suppressed turbulence despite wall shear stresses two to four orders of magnitude higher than in water, a finding incompatible with boundary-layer diffusion control, where a stagnant fluid layer adjacent to the vesicle surface limits mass transfer. Instead, the data support the proposed shear-shielding mechanism in which the colloidal matrix attenuates mechanical stress transmission to the vesicle. These results challenge the prevailing boundary-layer interpretation of colloid-mediated release retardation and highlight the need for shear-aware in vitro models in liposomal formulation design.