For nanomedicine, sex matters

(Nanowerk Spotlight) When experimental biomedical research results using only one sex are extrapolated to both sexes, unintended harmful consequences to the neglected sex can be the result. This has been known since the 1990s, when the importance of sex as a biological variable in laboratory and clinical experiments was recognized by the biomedical research community.
Here is what a report ("Most Drugs Withdrawn in Recent Years Had Greater Health Risks for Women") by the U.S. Government Accountability Office (GAO) found in 2001: During the time period from 1997 to 2000, ten prescription drugs were withdrawn from the market by the US Food and Drug Administration (FDA). Eight of the withdrawn drugs caused greater health risks in women. Looking in detail, four of the drugs caused more adverse events in women because they were prescribed more often to women than to men. However, the other four drugs had more detrimental effects in women, even though they were equally prescribed to both women and men, suggesting that physiological differences between males and females predispose women to some adverse drug-related health risks.
Nevertheless, it is still the case that only a small number of published articles report the sex of biosystems used in their study.
Please note that the term sex refers to the biological trait and not the gender or social identity of individuals. Although the terms sex and gender might be used exchangeably, they have different meanings. According to the Canadian Institutes of Health Research (CIHR), "Sex refers to a set of biological attributes in humans and animals. It is primarily associated with physical and physiological features including chromosomes, gene expression, hormone levels and function, and reproductive/sexual anatomy. Gender refers to the socially constructed roles, behaviors, expressions and identities of girls, women, boys, men, and gender diverse people."
"Many researchers are still using only one sex of biosystems – e.g., cells, tissues, or animals – and apply the results to both males and females," Morteza Mahmoudi, an Assistant Professor in the Precision Health Program at Michigan State University, tells Nanowerk. "And with the emergence of nanomedicine, the importance of sex in biomedical research has become even more obvious."
A recent review in Nature Communications ("Sex as an important factor in nanomedicine"), led by Mahmoudi and Dr. Sara Sheibani at McGill University, finds that the nanomedicine literature lacks robust information on the role of sex on the safety and therapeutic efficacy of nano-based therapeutics.
schematic of sex-dependent physiological differences
Sex-dependent physiological differences. Schematic representation of male/female differences in (A) DNA methylation, (B) sex chromosomes, (C) metabolome, lipidome, and proteome, (D) immune cells, (E) hormone production (during E1) pregnancy, E2 menopause, E3 puberty, (F) plasma composition, (G) mosaicism, and (H) X-chromosome inactivation. (Reprinted from Nature Communications under a Creative Commons Attribution 4.0 International License) (click on image to enlarge)
In their article, the authors focus on how sex-dependent physiological differences can affect the interaction of nanoparticles with biosystems and they mention some examples: "Although only a handful of nanomedicine studies have focused on the sex-dependent effects of nanoparticles, results indicate that the same nanoparticles have different therapeutic and toxic impacts in male and female animals. For example, PEG-coated gold nanoparticles show different toxic effects in male and female mice, producing more severe kidney damage in females, but higher liver toxicity in males. In another study, amorphous silica nanoparticles triggered more-severe inflammation and lung tissue damage in female rats compared to male rats."
In previous Nanowerk Spotlights we wrote about the role of the biomolecular corona – biomolecules forming a coating layer on the surface of nanoparticles – and the associated fact that the properties of a therapeutic nanoparticle can change – to an unknown degree – simply by being introduced into the body.
Mahmoudi points out that biomedical researchers increasingly recognize that plasma composition (e.g., due to individual variations and health status) significantly affects nanoparticles' biomolecular protein corona profiles.
"Therefore, one can expect that sex-based biomolecular differences in any given plasma sample to be reflected in nanoparticle biomolecular/ protein corona composition," he says. "Although corona profiles have been widely investigated under a variety of conditions, to the best of our knowledge, few reports have considered the effect of sex on the composition and decoration of biomolecular/protein corona."
In their review, the authors also address sex-dependent toxicity and therapeutic efficacy of nanoparticles such as sex-specific molecular and cellular structures; sex-specific biomolecules; sex-specific immunity; and sex-specific disease environments.
A particular hot topic in nanomedicine at the moment are the mRNA-based vaccines against COVID-19 (e.g., BioNTech-Pfizer, Moderna, CureVac) that use lipid-based nanoparticles. Early results of the clinical trials of these nanomedicine-based vaccines revealed equally better performance in both males and females.
"While the sex-specific efficacy outcomes of these vaccines should be continuously monitored and reported, more fundamental studies are required to be conducted on the sex-specific efficacy of the nanomedicine-based vaccines at cellular and molecular levels," says Mahmoudi.
"The outcomes of such efforts will help the scientific community to better define potential sex-dependent therapeutic/toxic effect of COVID-19 vaccines, which in turn pave a way for development of other sex-specific nanomedicine vaccines design, development, and administration," he concludes.
He notes that there are many challenges to overcome before the importance of sex can be systematically considered in studies and reports. Accordingly, in the final segment of their review, the authors outline the central challenges and propose possible strategies to address them.
By Michael is author of three books by the Royal Society of Chemistry:
Nano-Society: Pushing the Boundaries of Technology,
Nanotechnology: The Future is Tiny, and
Nanoengineering: The Skills and Tools Making Technology Invisible
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