Upconversion nanoparticles (UCNPs) have been widely employed in biosensing, bioimaging, photodynamic therapy and drug delivery in the past ten years. Presently, upconversion nanoparticles are obtained via thermal decomposition, co-precipitation, and solvothermal methods with oleylamine or oleic acid as surfactants always have low size dispersity, strong luminescence and disperse well in nonpolar solvents like cyclohexane. However, these kinds of nanoparticles are normally covered by a layer of oleic acid or oleylamine molecules, and hence are not suitable for directly using in biological environments. The subsequent surface modification which can turn hydrophobic nanoparticles into hydrophilic ones is therefore required. These methods include ligand exchange, ligand oxidation, amphiphilic polymer coating, silica coating, and ligand removal and so on. This account throws a critical look at the methods for surface modification and functionalization that lead to UCNPs for use in aqueous media and discusses the advantages and disadvantages of these strategies.

Contents
1 Introduction
2 Surface modification
2.1 Ligand oxidation
2.2 Ligand exchange
2.3 Amphiphilic ligand coating
2.4 Ligand removal
2.5 Layer-by-layer assembly
2.6 Silica coating and silanization
3 Bioconjugation
3.1 Covalent conjugation
3.2 Electrostatic attraction
3.3 Van der Waals Bonding
3.4 Direct attachment of biomolecule to NP surface
4 Conclusion and outlook