Nanotoxicology meets smart polymers: advancing safety-by-design nanomaterials

Smart polymers have played great role in enhancing nanomedical application areas in drug delivery, diagnosis and environment sensitive treatment systems. Nonetheless, their highly adaptive and structurally diverse nature leads to more concern toward their methods of action and their safety in the nanoscale. Thus, this review seeks to provide an informed account of how smart polymers can act as vectors of biomedical advancement as well as drivers of biological interactions that have not had a favorable outcome. Using a PRISMA 2020-informed reporting principle, this work presents a narrative and critical synthesis of <i>in vitro</i> and <i>in vivo</i> investigating the nanotoxicology of smart polymer-based nanosystems. Accordingly, no formal meta-analysis was undertaken. Oxidative stress, immune response, and organ injury are observed as the critical issues, whereas the factors, including the surface modification of nanoparticles and biodegradation, are the significant predictors of safer nanoparticles. In addition, it highlights high-throughput screening, artificial intelligence based modeling and quantitative or physiologically based simulations as some of the promising approaches to predictive toxicology to support safe-by-design strategies. These findings show that there is a need for polymer type regulation and ethical measures to promote safe use of smart polymers in future health care sectors.