Bioorthogonal transformations are chemical reactions that use pathways which biological processes do not access. Bioorthogonal chemistry provides new approaches for imaging and therapeutic strategies, as well as tools for fundamental biology. Bioorthogonal catalysis enables the development of bioorthogonal “factories” for on-demand and in situ generation of drugs and imaging tools. Transition metal catalysts (TMCs) are widely employed as bioorthogonal catalysts due to their high efficiency and versatility. The direct application of TMCs in living systems is challenging, however, due to their limited solubility, instability in biological media and toxicity. Incorporation of TMCs into nanomaterial scaffolds can be used to enhance aqueous solubility, improve long-term stability in biological environment and minimize cytotoxicity. These nanomaterial platforms can be engineered for biomedical applications, increasing cellular uptake, directing biodistribution, and enabling active targeting. This review summarizes strategies for incorporating TMCs into nanomaterial scaffolds, demonstrating the potential and challenges of moving bioorthogonal nanocatalysts and nanozymes toward the clinic.

Considering nanogels, we have focused our attention on hybrid nanosystems for drug delivery and biomedical purposes. The distinctive strength of these structures is the capability to join the properties of nanosystems with the polymeric structures, where versatility is strongly demanded for biomedical applications. Alongside with the therapeutic effect, a non-secondary requirement of the nanosystem is indeed its biocompatibility. The importance to fulfill this aim is not only driven by the priority to reduce, as much as possible, the inflammatory or the immune response of the organism, but also by the need to improve circulation lifetime, biodistribution, and bioavailability of the carried drugs. In this framework, we have therefore gathered the hybrid nanogels specifically designed to increase their biocompatibility, evade the recognition by the immune system, and overcome the self-defense mechanisms present in the bloodstream of the host organism. The works have been essentially organized according to the hybrid morphologies and to the strategies adopted to fulfill these aims: Nanogels combined with nanoparticles or with liposomes, and involving polyethylene glycol chains or zwitterionic polymers.