Nanoparticle-Protein Corona Formation Challenges Targeting Accuracy in Nanomedicine

By Nanolect | Research News

Keywords: protein corona, nanomedicine targeting, nano–bio interfaces, translational nanotechnology, nanoparticle toxicity

Upon introduction into biological systems, the meticulously crafted surfaces of nanoparticles seldom remain unaltered. Instead, they are swiftly enveloped by a heterogeneous layer of adsorbed biomolecules, predominantly proteins, together with lipids and metabolites constituting what is referred to as the protein or biomolecular corona. Previously regarded as a minor occurrence, corona formation is now acknowledged as a critical determinant influencing nanoparticle behavior in vivo, with direct implications for targeting precision, immunological recognition, and clinical use.

Fig. Illustration of the proton coronona challange

A recently obtained biological identity

Nanoparticles are generally functionalized with ligands, antibodies, or polymers designed to provide selectivity for sick cells or molecular targets. Nonetheless, research across several nanomaterial categories consistently demonstrates that these synthetic identities are rapidly substituted upon contact with blood or serum. Proteins include albumin, immunoglobulins, complement factors, and apolipoproteins rapidly adsorb onto nanoparticle surfaces, establishing a dynamic biological interface that cells engage with rather than the initial design.

This approach fundamentally transforms the perception of nanoparticles by biological systems. The composition of the corona is significantly influenced by nanoparticle size, surface charge, curvature, and functionalization. Ultrasmall nanoparticles can engage with specific protein epitopes, but bigger particles function more as expansive surfaces that facilitate significant protein adsorption and, in certain instances, induce structural alterations in the bound proteins. These interactions are regulated by noncovalent forces electrostatic attraction, hydrophobic interactions, and hydrogen bonding situating the phenomena at the convergence of nanotechnology and supramolecular chemistry.

Consequences for targeting accuracy

Targeted nanomedicine is predicated on the premise that surface-attached ligands retain accessibility and functionality in physiological environments. Growing experimental data contests this idea. In protein-dense settings, targeting moieties are often sterically obstructed by the corona, diminishing receptor-specific interaction and diverting nanoparticles to off-target cells.

The diminished precision is especially concerning in cancer nanomedicine, where targeted accumulation in tumors is crucial. Preclinical investigations consistently show robust targeting efficacy in simple buffer systems, although significant declines in specificity are noted when nanoparticles interact with biological fluids. These findings elucidate the reasons for the restricted tumor accumulation of numerous nanotherapeutic systems in vivo, despite their encouraging in vitro outcomes.

Dynamic and disease-specific coronas

The protein corona is dynamic. The composition changes over time as proteins with greater binding affinity replace those that initially adsorb, a process governed by both kinetics and thermodynamics. Recently, focus has shifted to the influence of illness status on corona composition. Inflammatory circumstances significantly modify plasma protein profiles, resulting in coronas enriched with acute-phase proteins, coagulation factors, and immune-related molecules.

Experimental models of systemic inflammation indicate that illness progression can alter corona fingerprints and significantly affect immune cell interactions. In certain situations, nanoparticles may unintentionally activate immunological signaling pathways, modify cytokine profiles, or undergo increased clearance by phagocytic cells. The findings indicate that corona development is both nanoparticle-specific and contingent upon the patient and condition, hence adding complexity to tailored nanomedicine.

Biologically-informed design

Initial attempts to inhibit protein adsorption, particularly using polyethylene glycol (PEG) coatings, have had inconsistent outcomes. Although PEGylation can diminish nonspecific contacts, it does not eradicate corona formation. Consequently, the discipline is progressively transitioning towards techniques that recognize and integrate the consequences of the coronavirus instead of seeking to circumvent them.

Innovative methodologies encompass the intentional creation of "pre-defined" coronas, the application of biomimetic or zwitterionic surfaces, and the incorporation of corona characterization into initial nanoparticle evaluation. Recent advancements in proteomics, lipidomics, and high-resolution spectroscopy enable comprehensive research of corona composition, offering essential understanding of nanoparticle behavior in intricate biological contexts.

A primary translational obstacle

The acknowledgment that nanoparticle functionality is determined by their acquired biological identity undermines a fundamental premise of nanomedicine: that intentional surface design directly correlates with predictable in vivo efficacy. Nanoparticle behavior arises from a complicated interaction between material characteristics and biological environment.

As regulatory bodies place greater importance on the characterisation of nano-bio interfaces, comprehending protein corona formation is becoming crucial for translational success. Future advancements will likely rely on interdisciplinary collaborations that merge nanomaterials research, systems biology, immunology, and clinical expertise. By engineering nanoparticles with biological complexity as a consideration rather than an obstacle, the science may surmount one of its most enduring challenges to clinical efficacy.

In nanomedicine, targeting accuracy is not defined solely by design but by the biological identity nanoparticles acquire in real physiological environments.

References

Kopp, M., Kollenda, S., & Epple, M. (2017). Interactions between nanoparticles and proteins: Therapeutic strategies and supramolecular chemistry. Accounts of Chemical Research, volume 50, pages 1383–1390. https://doi.org/10.1021/acs.accounts.7b00051

Shaw, J. R., et al. (2025). The evolution of inflammatory illness influences the immune activation profiles mediated by the biomolecular corona of nanoparticles. Nature Communications, volume 16, page 924. https://doi.org/10.1038/s41467-025-56210-4

---------------------------------------------------------------------------------------------------------------------------

Nanolect Disclaimer

The content published on Nanolect is intended solely for informational and educational purposes. This article represents an independent interpretation and critical synthesis of peer-reviewed scientific literature. Nanolect does not reproduce copyrighted text, figures, or proprietary data from original publications.

The information presented does not constitute medical, clinical, legal, or professional advice, and should not be used as a substitute for consultation with qualified professionals. Scientific findings discussed may evolve as new evidence emerges. Nanolect assumes no responsibility for the interpretation or application of the information contained herein.