Conspectus
Functional
ligands consist of a wide range of small or large molecules
that exhibit a spectrum of physical, chemical, and biological properties.
A suite of small molecules (e.g., peptides) or macromolecular ligands
(e.g., antibodies and polymers) have been conjugated to particle surfaces
for specific applications. However, postfunctionalization of ligands
often presents challenges in controlling the surface density and may
require the chemical modification of ligands. As an alternative option
to postfunctionalization, our work has focused on using functional
ligands as building blocks to assemble particles while maintaining
their intrinsic (functional) properties. Through self-assembly or
template-mediated assembly strategies, we have developed a range of
protein-, peptide-, DNA-, polyphenol-, glycogen-, and polymer-based
particles. This Account discusses the assembly of such nanoengineered
particles, which includes self-assembled nanoparticles, hollow capsules,
replica particles, and core–shell particles, according to three
categories of functional ligands (i.e., small molecules, polymers,
and biomacromolecules) that are used as building blocks for their
formation. We discuss a range of covalent and noncovalent interactions
among ligand molecules that have been explored to facilitate the assembly
of particles. The physicochemical properties of the particles, including
size, shape, surface charge, permeability, stability, thickness, stiffness,
and stimuli-responsiveness, can be readily controlled by varying the
ligand building block or by tuning the assembly method. By selecting
specific ligands as building blocks, the bio–nano interactions
(i.e., stealth, targeting, and cell trafficking) can also be modulated.
For instance, particles composed mainly of low-fouling polymers (i.e.,
poly(ethylene glycol)) exhibit an extended blood circulation time
(half-life > 12 h), while antibody-based nanoparticles demonstrate
that a trade-off between stealth and targeting may be required when
designing targeting nanoparticle systems. Small molecular ligands,
such as polyphenols, have been used as building blocks for particle
assembly as they can interact with various biomacromolecules through
multiple noncovalent interactions, retain the function of biomacromolecules
within the assembly, enable pH-responsive disassembly when coordinating
with metal ions, and facilitate endosomal escape of nanoparticles.
A perspective is provided on the current challenges associated with
the clinical translation of ligand-based nanoparticles. This Account
is also expected to serve as a reference to guide the fundamental
research and development of functional particle systems assembled
from various ligands for diverse applications.