Nanogel Functionalization: A Versatile Approach To Meet the Challenges of Drug and Gene Delivery

Abstract

The design of nanostructures carrying therapeutic molecules represents the new frontier in the biological and medical fields. In particular, researchers have identified nanogels as promising tools in response to the critical issues of intracellular delivery: because of their peculiar properties, including swelling behavior, nanogels are able to cross the cellular membrane (clathrin-mediated endocytosis, caveolin-mediated endocytosis, phagocytosis, and macropinocytosis) and release their cargo in the cytosol, avoiding the activation of immune responses. However, only the combination of different starting polymers is not enough for the development of selective and targeted nanocarriers. The orthogonal functionalization of polymer chains with different chemical groups allows grafting of specific moieties and conjugating biomolecules, such as peptides, proteins, and growth factors, to give rise to nanogels that are not only more attractive but also more efficient in drug and gene delivery, with the ability to reach specific sites and trigger selective therapies. Moreover, the functionalization techniques offer the opportunity to improve load protection until the desired area is reached and synthesize nanosystems that are sensitive to biological stimuli. This review discusses the key role of nanogel functionalization to design promising nanonetworks for drug and gene delivery, highlighting how modification of the polymer meets the challenges of biomolecule transport, and summarizes the most recent results recorded in these fields. A brief mention is also accorded to the functionalization approach to produce detectable nanogels in vitro and in vivo, ensuring their traceability over time.

Coating and Functionalization Strategies for Nanogels and Nanoparticles for Selective Drug Delivery

“…As in the case of nanoparticles, various strategies are also available for the preparation of cross-linked nanogels [30]. First of all, we have to consider the synthesis through chemical reaction that involves a heterogeneous polymerization of low-molecular-weight monomers or the cross-linking of polymer precursors [31,32].…”

Micro and Nanogels for Biomedical Applications

“…Micro and nanogels are excellent nominees to conventional dosage forms of drugs as they are one such class of resourceful materials with convenient suitability for biomedical applications primarily because of their softness, high water content, high surface area, and payload capacity, tunable size, biocompatibility and other advantages. Despite these superiorities, micro and nanogels still face some issues and pitfalls complicating their ideal implementation into clinical utilization such as inadequacy of efficient and stable drug encapsulation without leakage in compelling microenvironment of tissues over extended time periods and consequent toxicity issues leading to decrease in treatment efficiency [83]. Beside premature drug release, due to high surface energy of microgels and nanogels, they adsorb proteins in the serum and can be steadily opsonized and eliminated by mononuclear phagocyte system (depending on the particle size, charge, and shape) without achieving aimed drug release.…”

Polyethylenimine‐Based Nanogels for Biomedical Applications

“…In general, PEI‐based NG vectors bind DNA or RNA electrostatically and condense the genetic materials to form particles with a small size to protect genes and mediate cellular uptake. Moreover, PEI‐based NGs can recognize specific cell types by conjugation of targeting ligands such as galactose, mannose, transferrin, and antibodies onto the NG surfaces. Both plasmid DNA and small interfering RNA (siRNA) have been frequently involved for gene therapies of numerous diseases such as cancer, neurodegenerative disorders, and viral infections through the selective inhibition of messenger RNA (mRNA) sequences …”