Osmolytes are small
organic compounds accumulated at higher concentrations
in the cell under various stress conditions like high temperature,
high salt, high pressure, etc. Osmolytes mainly include four major
classes of compounds including sugars, polyols, methylamines, and
amino acids and their derivatives. In addition to their ability to
maintain protein stability and folding, these osmolytes, also termed
as chemical chaperones, can prevent protein misfolding and aggregation.
Although being efficient protein folders and stabilizers, these osmolytes
exhibit certain unavoidable limitations such as nearly molar concentrations
of osmolytes being required for their effect, which is quite difficult
to achieve inside a cell or in the extracellular matrix due to nonspecificity
and limited permeability of the blood–brain barrier system
and reduced bioavailability. These limitations can be overcome to
a certain extent by using smart delivery platforms for the targeted
delivery of osmolytes to the site of action. In this context, osmolyte-functionalized
nanoparticles, termed nano-osmolytes, enhance the protein stabilization
and chaperone efficiency of osmolytes up to 105 times in
certain cases. For example, sugars, polyols, and amino acid functionalized
based nano-osmolytes have shown tremendous potential in preventing
protein aggregation. The enhanced potential of nano-osmolytes can
be attributed to their high specificity at low concentrations, high
tunability, amphiphilicity, multivalent complex formation, and efficient
drug delivery system. Keeping in view the promising potential of nano-osmolytes
conjugation in tailoring the osmolyte–protein interactions,
as compared to their molecular forms, the present review summarizes
the recent advancements of the nano-osmolytes that enhance the protein
stability/folding efficiency and ability to act as artificial chaperones
with increased potential to prevent protein misfolding disorders.
Some of the potential nano-osmolyte aggregation inhibitors have been
highlighted for large-scale screening with future applications in
aggregation disorders. The synthesis of nano-osmolytes by numerous
approaches and future perspectives are also highlighted.