Control of interactions between nanoparticles and biosystems is essential for the effective utilization of these materials in biomedicine. A wide variety of nanoparticle surface structures have been developed for imaging, sensing, and delivery applications. In this research Highlight, we will emphasize advances in tailoring nanoparticle interfaces for implementation in nanomedicine.

There is a direct correlation between protein levels and disease states in human serum making it an attractive target for sensors and diagnostics. However this is made challenging because serum features more than 20,000 proteins with an overall protein content of greater than 1 mM. Here we report a hybrid synthetic-biomolecule based sensor that uses green fluorescent protein-nanoparticle arrays to detect proteins at biorelevant concentrations in both buffer and human serum. Distinct and reproducible fluorescence response patterns were obtained from five serum proteins (human serum albumin, immunoglobulin G, transferrin, fibrinogen and α-antitrypsin) in buffer and when spiked into human serum. Using linear discriminant analysis we identified these proteins with an identification accuracy of 100% in buffer and 97% in human serum. The arrays were also able to discriminate between different concentrations of the same protein as well as a mixture of different proteins in human serum.

Gold nanoparticles (AuNPs) provide attractive vehicles for delivery of drugs, genetic materials, proteins, and small molecules. AuNPs feature low core toxicity coupled with the ability to parametrically control particle size and surface properties. In this review, we focus on engineering of the AuNP surface monolayer, highlighting recent advances in tuning monolayer structures for efficient delivery of drugs and biomolecules. This review covers two broad categories of particle functionalization, organic monolayers and biomolecule coatings, and discusses their applications in drug, DNA/RNA, protein and small molecule delivery.

Intracellular protein delivery is an important tool for both therapeutic and fundamental applications. Effective protein delivery faces two major challenges: efficient cellular uptake and avoiding endosomal sequestration. We report here a general strategy for direct delivery of functional proteins to the cytosol using nanoparticle-stabilized capsules (NPSCs). These NPSCs are formed and stabilized through supramolecular interactions between the nanoparticle, the protein cargo, and the fatty acid capsule interior. The NPSCs are ~130 nm in diameter and feature low toxicity and excellent stability in serum. The effectiveness of these NPSCs as therapeutic protein carriers was demonstrated through the delivery of fully functional caspase-3 to HeLa cells with concomitant apoptosis. Analogous delivery of green fluorescent protein (GFP) confirmed cytosolic delivery as well as intracellular targeting of the delivered protein, demonstrating the utility of the system for both therapeutic and imaging applications.

The application of nanomaterials to detect disease biomarkers is giving rise to ultrasensitive assays, with scientists exploiting the many advantageous physical and chemical properties of nanomaterials. The fundamental basis of such work is to link unique phenomena that arise at the nanoscale to the presence of a specific analyte biomolecule, and to modulate the intensity of such phenomena in a ratiometric fashion, in direct proportion with analyte concentration. Precise engineering of nanomaterial surfaces is of utmost importance here, as the interface between the material and the biological environment is where the key interactions occur. In this tutorial review, we discuss the use of plasmonic nanomaterials in the development of biodiagnostic tools for the detection of a large variety of biomolecular analytes, and how their plasmonic properties give rise to tunable optical characteristics and surface enhanced Raman signals. We put particular focus on studies that have explored the efficacy of the systems using physiological samples in an effort to highlight the clinical potential of such assays.

Discovering therapeutic inorganic nanoparticles is evolving as an important area of research in the emerging field of nanomedicine. Recently, we reported the anti-angiogenic property of gold nanoparticles (GNPs): it inhibits the function of pro-angiogenic heparin-binding growth factors (HB-GFs) such as vascular endothelial growth factor 165 (VEGF165), basic fibroblast growth factor (bFGF), etc. However, the mechanism through which GNP imparts such an effect remains to be investigated. Using GNPs of different sizes and surface charges we demonstrate here that a naked GNP surface is required and core size plays an important role to inhibit the function of HB-GFs and subsequent intracellular signaling events. We also demonstrate that the inhibitory effect of GNPs is due to the change in HB-GFs conformation/configuration (denaturation) by the nanoparticles, whereas the conformations of non-HB-GFs remain unaffected. Significantly, this study will help structure-based design of therapeutic nanoparticles to inhibit the functions of disease causing proteins.

Nanoparticle-based platforms for identification of chemical and biological agents offer substantial benefits to biomedical and environmental science. These platforms benefit from the availability of a wide variety of core materials as well as the unique physical and chemical properties of these nanoscale materials. This review surveys some of the emerging approaches in the field of nanoparticle based detection systems, highlighting the nanoparticle based screening methods for metal ions, proteins, nucleic acids, and biologically relevant small molecules.

The binding of bovine serum albumin (BSA) and β-lactoglobulin (BLG) to TTMA (a cationic gold nanoparticle coupled to 3, 6, 9, 12-Tetraoxatricosan-1-Aminium, 23-mercapto-N, N, N-TriMethyl)- was studied by high-resolution turbidimetry (to observe a critical pH for binding), dynamic light scattering (to monitor particle growth), and isothermal titration calorimetry (to measure binding energetics), all as a function of pH and ionic strength. Distinctively higher affinities observed for BLG vs. BSA, despite the lower pI of the latter, were explained in terms of their different charge anisotropies, namely the negative charge patch of BLG. To confirm this effect, we studied two isoforms of BLG that differ in only two amino acids. Significantly stronger binding to BLGA could be attributed to the presence of the additional aspartates in that negative charge domain for dimer, best portrayed in DelPhi. This selectivity decreases with ionic strength, for which both isoforms bind well below pI, but increases with ionic strength for BLG vs. BSA which binds above pI. This result points to the diminished role of long-range repulsions for binding above pI. Dynamic light scattering reveals a tendency for higher-order aggregation for TTMA–BSA at pH above the pI of BSA, due to its ability to bridge nanoparticles, whereas soluble BLG–TTMA complexes were stable over a range of pH because the charge anisotropy of this protein at pH < pI makes it unable to bridge nanoparticles. Finally, isothermal titration calorimetry shows endoenthalpic binding for all proteins; the higher affinity of TTMA for BLGA vs. BLGB comes from a difference in the dominant entropy term.