Synthesis and Applications of Colloidal Nanobioconjugates with Modular Multivalency: A Review

Nanobioconjugates are extensively employed in an array of biomedical applications, such as photodynamic therapy materials, drug delivery carriers, bioimaging probes, single molecule tracking, detection probes, and brain targeting agents through transcytosis. To provide these biological applications, nanoparticles need to be designed delicately with specific targeting ligands to recognize specific molecules or to target specific receptors over the cell’s surface, and this cellular internalization process generally follows a receptor-mediated endocytosis pathway. The variables that govern this interaction as well as the cellular entry/exit process are the size and shape of the nanoparticle, surface chemistry and surface charge of the nanoparticle, and nanoparticle multivalency (the number of targeting ligands on the nanoparticle surface). Herein, we elaborately discuss the nanoparticle multivalency parameter. Monovalent nanobioconjugates always interact with cell receptors through 1:1 interaction and reduce receptor clustering, which is inefficient for nanoparticle internalization. In the case of multivalent nanobioconjugates, this interaction occurs through multiple ligands from one nanoparticle with multiple receptors on the cell surface, which leads to receptor clustering. However, nanobioconjugates with uncontrolled multivalency reduce receptor mobility, followed by lysosomal trapping, and fail for proper biomedical applications. Therefore, the development of nanobioconjugates with modular or controlled multivalency is much more challenging and is also needed for different biomedical applications. Throughout this review, we describe the crucial role of nanoparticle multivalency in different biomedical applications. Next, we discuss various synthesis approaches to develop monovalent nanobioconjugates via a surface masking strategy and streptavidin–biotin interaction. Moreover, we discuss how nanoparticle multivalency can be controlled by using a competitor of targeting ligand, by regulating the size of the nanoparticle, and by changing the reaction medium/reaction condition. Next, we demonstrate how nanoparticle multivalency directs the cellular entry–exit mechanism, subcellular targeting, and brain targeting. Finally, we discuss the application and effect of multivalent nanobioconjugates in drug delivery, tumor targeting, single-molecule imaging, and detection of cancer cells/proteins/peptides.