In the rapidly evolving field of nanomedicine, scientists are engineering ultra-small particles to deliver therapeutic agents directly to diseased tissues and cells, enhancing treatment efficacy while minimizing collateral damage. This targeted approach has already proven successful in clinically approved RNA-based technologies and chemotherapy formulations. However, designing effective nanomedicines presents significant challenges, particularly regarding how the body’s immune system perceives and processes these foreign particles.
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The immune system often mistakes nanoparticles for harmful invaders, triggering clearance mechanisms that limit therapeutic effectiveness and sometimes cause adverse effects. Central to this biological response is the protein corona—a dynamic layer of proteins that spontaneously forms around nanoparticles upon entering the bloodstream. Recent investigations into protein coatings have revealed their profound influence on how immune cells recognize nanoparticles and whether these particles can successfully reach their intended destinations.
“Understanding how the protein corona influences a nanoparticle’s journey through the body will enable us to design nanomedicines that more reliably evade immune detection and deliver therapies with precision,” explained senior author Emily Day, professor in the Department of Biomedical Engineering at the University of Delaware College of Engineering. Her team’s findings, published September 29 in the Proceedings of the National Academy of Sciences, provide crucial insights into this complex interaction.
Targeting the Body’s Blood Production Factories
For this groundbreaking study, researchers focused specifically on nanoparticles designed to target hematopoietic stem cells—the rare progenitor cells responsible for generating all blood cell types. Nanomedicines capable of delivering drugs or gene therapies directly to these cells could revolutionize treatments for conditions ranging from bone marrow transplantation preparation to genetic disorders like sickle cell disease.
“The extreme rarity of hematopoietic stem cells—comprising just 0.01% of bone marrow cells—makes them exceptionally challenging to target,” said first author Eric Sterin, who recently earned his doctorate in biomedical engineering from UD. “To improve targeted delivery, we’ve been experimenting with wrapping nanoparticles in membranes derived from bone marrow cells called megakaryocytes, which coats them with proteins that naturally guide them toward bone marrow.”
The research team conducted extensive laboratory and animal experiments to understand how these membrane-wrapped nanoparticles behave in biological systems. To simulate real-world conditions, they incubated the particles in blood serum from mice, cows, and humans to form protein coronas. The results revealed striking differences: compared to unwrapped nanoparticles, membrane-wrapped particles bound significantly less protein overall, and in human serum, the classes of proteins that adhered to them were particularly distinct.
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Protein Corona Composition Determines Cellular Interactions
Further experimentation demonstrated that the sparser protein coronas on membrane-wrapped particles significantly influenced their cellular interactions. In laboratory studies, these specially coated particles not only entered their target cells more efficiently but were also less likely to be engulfed by immune cells compared to their unwrapped counterparts. This dual advantage suggests that strategic protein corona engineering could substantially improve nanomedicine performance.
The researchers then delved deeper into understanding which specific proteins within the corona exert the greatest influence on nanoparticle fate. Proteomics analyses yielded a surprising discovery: apolipoprotein B emerged as the most abundant protein in the corona, contrary to previous studies with similar nanoparticles that had identified apolipoprotein E as dominant. Both proteins function as molecular transporters throughout the body but can also serve as recognition “flags” that make nanoparticles more visible to clearance mechanisms.
As researchers explore these biological frontiers, global scientific challenges continue to demand innovative solutions across multiple disciplines, including materials science and biomedical engineering.
Balancing Act: Immune Clearance Versus Targeted Delivery
To investigate how individual corona proteins affect nanoparticle destiny, the team employed specialized mouse models, each genetically engineered to lack specific proteins. Tracking particle distribution after injection revealed a delicate biological balancing act. Certain proteins in the corona, including complement component 3 and immunoglobulin G, were found to facilitate immune-mediated particle clearance to organs like the liver. Paradoxically, these same proteins also appeared to assist particles in reaching targeted hematopoietic stem cells within bone marrow.
“Finding methods to control the levels of these proteins could help shift the balance toward more precise delivery to blood stem cells in the bone marrow and reduce off-target delivery to other organs,” Day noted. This nuanced understanding of protein corona dynamics represents a significant advancement in nanomedicine design principles.
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Future Directions and Engineering Applications
Current research efforts focus on manipulating protein corona composition by altering components of the membrane wrapping. The team plans to extend their experiments to humanized mouse models, which feature human-like immune systems, to better predict how these engineered nanoparticles might perform in human patients. This approach could accelerate the translation of laboratory findings into clinical applications.
Meanwhile, parallel advances in computational power are enabling more sophisticated simulations of nanoparticle behavior. Recent breakthroughs in compiler technology that enhance GPU offloading capabilities demonstrate how computational advancements can accelerate scientific discovery across fields, including biomedical research.
The implications of this research extend beyond medicine to broader technological infrastructure. Just as major investments in data center infrastructure are creating new possibilities for information processing, strategic investments in nanomedicine infrastructure could revolutionize therapeutic delivery systems.
Collaborative efforts across disciplines continue to drive innovation, with industry leaders joining forces in open compute initiatives to develop next-generation hardware solutions that could eventually support the computational demands of complex biological simulations.
As nanoparticle engineering evolves, the precise control of protein coronas represents a promising frontier for improving targeted drug delivery. By harnessing the body’s natural protein interactions rather than fighting against them, researchers are developing smarter nanomedicines that can navigate the bloodstream more effectively, avoid immune detection, and deliver their therapeutic payloads with unprecedented precision.
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