Nanotoxicology and nanomedicine: The Yin and Yang of nano-bio interactions for the new decade

Highlights

• Nanotoxicology and nanomedicine are two pillars of nanotechnology, representing the Yin and Yang of nano-bio interactions.

• The applicability of nanotoxicology and the efficacy of nanomedicines may be improved by their knowledge transfer.

• Routes of knowledge transfer between the two sub-disciplines are outlined and recommended in this Review.

• A synergistic partnership between the two fields may benefit human and environmental health in the coming decade.

Abstract

Nanotoxicology and nanomedicine are two sub-disciplines of nanotechnology focusing on the phenomena, mechanisms, and engineering at the nano-bio interface. For the better part of the past three decades, these two disciplines have been largely developing independently of each other. Yet recent breakthroughs in microbiome research and the current COVID-19 pandemic demonstrate that holistic approaches are crucial for solving grand challenges in global health. Here we show the Yin and Yang relationship between the two fields by highlighting their shared goals of making safer nanomaterials, improved cellular and organism models, as well as advanced methodologies. We focus on the transferable knowledge between the two fields as nanotoxicological research is moving from pristine to functional nanomaterials, while inorganic nanomaterials – the main subjects of nanotoxicology – have become an emerging source for the development of nanomedicines. We call for a close partnership between the two fields in the new decade, to harness the full potential of nanotechnology for benefiting human health and environmental safety.

Introduction

Nanomaterials (NMs) and their functional derivatives have enabled a wide range of breakthroughs in technology, engineering and medicine, and the advent of nanotechnology is considered as important as the Industrial Revolution [1]. However, as with other innovative substances (e.g., pesticides or antibiotics), the commercialization of NMs preceded their extensive safety evaluation in relation to human and environmental health. Overlooking existing toxicological knowledge in the development of nanotechnologies, especially in biomedical applications, can be costly. Thus, the effective and safe use of nano-biomedical applications necessitates the development and partnership of the disciplines that are historically referred to as “nanotoxicology” and “nanomedicine”.

Nanotoxicology emerged when toxicologists in the 1990s extended their research from the pulmonary effects of airborne particles to these of engineered NMs such as metal oxides and carbon nanotubes (CNTs) [2], [3]. Nano(eco)toxicology was later supported by European legislation mandating systematic studies on the toxicity of NMs [4]. To date, nanotoxicology has developed into a relatively mature discipline, generating systematic knowledge for risk assessment of NMs and for the development of safer-by-design nano-enabled products, which are also an integral part of the processes needed for successful clinical translation of nanomedicines.

The development of nanomedicine was driven by the progress in the pharmaceutical industry in the 1960s that resulted in the development of NM-based systems for controlled drug release [5]. Despite the relatively long history of nanomedicine, there were only approximately 50 US Food and Drug Administration (FDA)-approved nanomedicines on the market and 77 in clinical trials in 2016 [6], most based on liposomes and protein complexes. Nanomedicine as a field has faced challenges in clinical translation, with the major obstacle being low efficacy due to limited understanding of nano-bio interactions, NM biocompatibility, NM-specific toxicity, targeted delivery and NM fate and degradation [7].

Despite apparent differences in definition, nanotoxicology and nanomedicine are both fundamentally focused on the dose-response relationship of NMs. Nanotoxicology is concerned with determining the NM concentrations that cause unintended effects, i.e., toxicity, or cause toxicity to non-target cells, organs, or organisms. On the other hand, nanomedicine aims to increase the specificity and efficacy of drugs, bioimaging or diagnostic agents at the lowest possible doses. The favorable efficacy/toxicity ratio, tumor targeting and release tunability are major benefits of nanomedicines over conventional drugs and are thus important driving forces for the development of nanomedicine. In addition, from the perspective of nanomedicine, nanotoxicology has often been viewed as a discipline that provides toxicology information to guide the design of safer NMs and therefore has been suggested to be renamed as “nanosafety” [8]. However, within the context of this Review, we consider “nanosafety” as being a constituent of the broader definition of nanotoxicology that encompasses both unintended (for safety to human health and the environment) and intended (for nanodrug efficacy) toxicity of NMs, and use the term “nanotoxicology” here to signify primarily the investigation of the unintended effects of NMs.

The goal of this Review is to demonstrate that nanotoxicology and nanomedicine share many overlapping interests and challenges (Scheme 1), and bridging these two disciplines, accordingly, would be mutually beneficial. From the viewpoint of nanotoxicology, nanomedicine is a major outlet for applying existing knowledge and elevating the translational value of nanotoxicology through advocating safer and more efficacious NMs for medicine. Conversely, nanomedicine can benefit from existing knowledge and methodologies of nanotoxicology, from NM-cell interactions, complex mixture characterization techniques and cellular and organism models to the chemical and biological effects arising from the interplay of physicochemical properties of NMs on their exposure, biodistribution, biotransformation, accumulation, and toxicity. Moreover, considering the importance of the microbiome in human diseases, as recently revealed, the expertise of nano(eco)toxicology has become precipitously relevant to the development of nanomedicine targeting cancer, neurological disorders as well as metabolic diseases. In addition, we elaborate on the idea that engineered nanoparticles can be exploited in different ways to fight biological nanoparticles such as coronaviruses, using the complementary know-how of nanotoxicology and the pragmatic approaches of nanomedicine. Thus, both disciplines would gain from the transfer of knowledge and sharing of cellular and organism models as well as analytical techniques as delineated in this article.