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WIREs Nanomed Nanobiotechnol
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Precision engineering of targeted nanocarriers

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Since their introduction in 1980, the number of advanced targeted nanocarrier systems has grown considerably. Nanocarriers capable of targeting single receptors, multiple receptors, or multiple epitopes have all been used to enhance delivery efficiency and selectivity. Despite tremendous progress, preclinical studies and clinically translatable nanotechnology remain disconnected. The disconnect in targeting efficacy may stem from poorly‐understood factors such as receptor clustering, spatial control of targeting ligands, ligand mobility, and ligand architecture. Further, the relationship between receptor distribution and ligand architecture remains elusive. Traditionally, targeted nanocarriers were engineered assuming a “static” target. However, it is becoming increasingly clear that receptor expression patterns change in response to external stimuli and disease progression. Here, we discuss how cutting‐edge technologies will enable a better characterization of the spatiotemporal distribution of membrane receptors and their clustering. We further describe how this will enable the design of new nanocarriers that selectively target the site of disease. Ultimately, we explore how the precision engineering of targeted nanocarriers that adapt to receptor dynamics will have the potential to drive nanotechnology to the forefront of therapy and make targeted nanomedicine a clinical reality. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Biology‐Inspired Nanomaterials > Lipid‐Based Structures Biology‐Inspired Nanomaterials > Protein and Virus‐Based Structures
Nanoparticle‐mediated receptor clustering affects endocytosis and downstream signaling. Clustering can be mediated between the same receptors (homo‐clustering) or different receptors (hetero‐clustering)
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Membrane fluidity allows clustering of targeting ligand 1 and 2 on fluid particles to respond to their respective receptor targets on cellular membranes. This can result in higher affinity and enhanced interactions with membrane receptors
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(a,b) DNA scaffold displaying two thrombin binding aptamers at varying distances. (b) Optimal thrombin binding is achieved when the distance between both aptamers is 5.3 nm. Image adapted from Rinker and colleagues (Rinker et al., ). (c,d) Spatially controlled display of targeting ligands on virus‐like capsids. The distance between the targeting ligands can be controlled through epitope targeting or genetic fusion and affects binding to cell membrane receptors. DTL = distance between targeting ligands, DR = distance between receptors. PDB code for virus particle: 3J40
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Biology-Inspired Nanomaterials > Protein and Virus-Based Structures
Biology-Inspired Nanomaterials > Lipid-Based Structures
Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Therapeutic Approaches and Drug Discovery > Emerging Technologies

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