Bioinspired Design Principles for Clearance-Resistant and Stress-Responsive Therapeutic Microcarrier - PROJECT SUMMARY/ABSTRACT Millions of patients worldwide are treated with intravenous drugs annually. To ensure efficacy while minimizing unnecessarily large doses that can cause adverse side effects, numerous nano/micro-particle-based therapeutic carriers have been developed. These particles deliver drugs to targeted disease sites for effective treatment with smaller drug amounts. However, up to 90% of these particles are cleared from the bloodstream by the immune system and biological filters (e.g., kidney, spleen), significantly reducing their effectiveness. This clearance often necessitates higher drug doses to ensure efficacy, reintroducing the risk of adverse side effects. In contrast, natural microparticles, such as red blood cells (RBCs), achieve remarkable circulation lifespans of up to 120 days, overcoming filtration and immune clearance through unique structural, mechanical, and biological properties. No synthetic systems have integrated these properties to achieve comparable clearance resistance— a serious gap that limits the biodistribution efficiency of drugs delivered via synthetic therapeutic carriers. This program will uncover principles by which RBC-inspired properties translate into synthetic carriers to evade biological clearance. Building on these insights, the program will investigate and integrate stress-responsive mechanisms into clearance-resistant microcarriers to enhance drug retention, enable controlled release, and improve biodistribution. Leveraging investigator expertise in single-molecule biophysics, artificial protein design and biosynthesis, and controlled self-assembly of protein-network materials, these questions will be addressed: 1) What principles enable synthetic systems to adapt to biological filters while maintaining structural integrity? By designing defect-minimized, robustly crosslinked, cytoskeletal-mimetic protein networks (CPNs) with diverse mechanical proteins, the team will engineer hollow CPN structures with adaptable yet resilient properties to navigate microchannels that mimic organ filters, including narrow, high-shear conditions of spleen filtration. 2) Which molecular strategies enable synthetic systems to evade immune clearance? By establishing orthogonal strategies to anchor immune-evasion shells (IES), including lipid bilayers, onto CPNs without compromising their mechanical properties, the team will construct RBC-inspired microparticles (RMs) with surface properties that shield them from proteolytic degradation and immune response. 3) How can synthetic systems retain drugs under physiological conditions and release them under pathological mechanical stresses? By elucidating how tailored mechanical proteins in CPNs drive stress-responsive pore dynamics and anchored IES stability, the team will develop RMs to retain drugs in physiological environments and release them in disease-altered mechanical stresses. The uncovered principles will lay the foundation for clearance-resistant, stress-responsive RM carriers as a synthetic drug delivery platform to improve biodistribution and inspire next-generation biomaterials, including artificial cells.
