Recent advances in the safety and toxicity assessment of polymeric nanocarriers: From physicochemical properties to clinical translation

Polymeric nanocarriers represent a promising drug delivery system for enhancing the solubility, bioavailability, stability, controlled release and targeted delivery of drugs. They possess special physicochemical properties that allow the transport of therapeutic agents with great efficacy across biological barriers without causing systemic side effects. A variety of natural and synthetic polymers, including chitosan, alginate, gelatin, collagen, albumin, poly (ethylene glycol) (PEG), polycaprolactone (PCL) and poly (lactic-co-glycolic acid) (PLGA) are commonly used for the production of polymeric nanocarriers. Although they have desirable therapeutic properties, there are still significant concerns about toxicity, biodistribution, immune response, and long-term safety when moving these technologies into the clinic. This review aims to briefly summarise the recent work on aspects of nanocarriers’ toxicity and to outline the effects of the nanocarriers’ physicochemical characteristics (size, shape, surface charge, zeta potential, surface chemistry, and polymer composition) on the biological interactions and toxicity of nanocarriers. The review also covers the mechanisms of toxicity at the cellular and molecular level, such as oxidative stress, generation of reactive oxygen species, cytotoxicity, genotoxicity, inflammation and immunotoxicity. In vitro and in vivo toxicity evaluation approaches, biodistribution studies and organ-specific toxicity are discussed to elucidate the safety profile of these systems. In addition, the function of biocompatibility/mimicking the surface of living tissue, biodegradability and reducing toxicity are discussed. The current agency timelines and perspectives on the safety evaluation of nanomedicine, from the FDA, EMA, and OECD, are also included. In conclusion, this review highlights the need for a systematic approach to toxicity testing and a safe-by-design approach in the development of polymeric nanocarrier and clinical translation.