Multivalent interactions in which multiple ligands on one object bind to multiple receptors on another are commonly found in natural biological systems. In addition, these interactions can lead to increased strength and selectivity when compared to the corresponding monovalent interaction. These attributes have also guided the design of synthetic multivalent ligands to control biological interactions. This review will highlight the recent literature describing the use of multivalent ligand display in the design of vaccines, immunomodulators, cell signaling effectors, and vehicles for targeted drug delivery.

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Despite the availability of licensed vaccines, influenza causes considerable morbidity and mortality worldwide. Current influenza vaccines elicit an immune response that primarily targets the head domain of the viral glycoprotein hemagglutinin (HA). Influenza viruses, however, readily evade this response by acquiring mutations in the head domain. While vaccines that target the more conserved HA stalk may circumvent this problem, low levels of antistalk antibodies are elicited by vaccination, possibly due to the poor accessibility of the stalk domain to B cell receptors. In this work, it is demonstrated that nanoparticles presenting HA in an inverted orientation generate tenfold higher antistalk antibody titers after a prime immunization and fivefold higher antistalk titers after a boost than nanoparticles displaying HA in its regular orientation. Moreover, nanoparticles presenting HA in an inverted orientation elicit a broader antistalk response that reduces mouse weight loss and improves survival after challenge to a greater extent than nanoparticles displaying HA in a regular orientation. Refocusing the antibody response toward conserved epitopes by controlling antigen orientation may enable the design of broadly protective nanovaccines targeting influenza viruses and other pathogens with pandemic potential.

Photoacoustic imaging using exogenous contrast agents has emerged as a hybrid technique that enables the deep imaging of optical properties of tissues with high spatial resolution. The power of this imaging technique can be greatly enhanced by the use of contrast agents that absorb at near-infrared wavelengths and whose optical properties can be modulated in response to the local environment. We have designed contrast agents consisting of gold nanoparticles coated with anisotropic silica nanoshells. The tunable aggregation of these janus particles in cell culture media resulted in a dramatic amplification of photoacoustic signals in the near-infrared region. We also demonstrated imaging using these contrast agents in mammalian cells, including macrophages and breast cancer cells as well as in vivo. The ability to modulate janus particle aggregation in response to a range of stimuli in combination with the high resolution and deep penetration of multiwavelength photoacoustic imaging are attractive for a broad range of applications in diagnostic imaging and theranostics.

3 The abbreviations used are: A␤, amyloid ␤; CDR, complementarity-determining region; scFv, single-chain variable fragment; V H , variable domain of heavy-chain; Fc, fragment crystallizable; HCDR3, heavy chain CDR3; BisTris, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol; IAPP, islet amyloid polypeptide; RCF, relative centrifugal force; APP, amyloid precursor protein; HFIP, hexafluoro-2-propanol; Ni-NTA, nickel-nitrilotriacetic acid; DMEM, Dulbecco's modified Eagle's medium; KLH, keyhole limpet hemocyanin; ssDNA, single-stranded DNA; RFU, relative fluorescence units. cro ARTICLE 8438 A␤ solubilization and fibril preparationA␤ peptides (biotin-A␤42 (AS-23523-05; Anaspec) and A␤42 (AS20276; Anaspec)) were initially dissolved in Nature-inspired anti-amyloid antibodies