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

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.