Navigating the Endothelial Barrier: A Multiscale Framework for Precision Nanomedicine.

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Vascular Biology

Background:

• The vascular endothelium acts as a critical barrier for systemic nanoparticle (NP) drug delivery.
• Current understanding of NP translocation across endothelium is limited, especially regarding nanoscale interactions and mesoscale events.
• Bridging the gap between molecular interactions and endothelial barrier dynamics is crucial for nanomedicine development.

Purpose of the Study:

• To provide a mechanistic framework linking nanoscale NP properties to mesoscale endothelial transport.
• To integrate insights from molecular interactions, junctional dynamics, and endothelial heterogeneity.
• To guide the rational design of nanomedicines for improved therapeutic efficacy and safety.

Main Methods:

• Analysis of multiscale vascular endothelium architecture and transport pathways (transcellular and paracellular).
• Physicochemical property analysis of NPs influencing molecular recognition at the endothelium.
• Utilizing molecular modeling and super-resolution imaging to identify predictive NP "nano-signatures".
• Investigating NP-induced mechanical changes in VE-cadherin and actomyosin networks.

Main Results:

• Identified NP "nano-signatures" that predict transport pathways across the endothelium.
• Demonstrated how NPs reprogram endothelial junctions, influencing paracellular leakage.
• Elucidated the role of NP transformations in modulating barrier penetration via interfacial interactions.
• Synthesized multiscale data into a cohesive mechanistic framework.

Conclusions:

• A mechanistic framework for NP-endothelial interactions was established.
• This framework provides a blueprint for designing safer and more effective nanomedicines.
• Understanding these interactions is key to enhancing therapeutic outcomes and minimizing adverse effects.