A nanoparticle may have little surface area, but it does represent a wide-open frontier in nanomedicine, which seeks to deploy nanoparticles in imaging, drug delivery, and cell reprogramming applications. In recent years, the discipline has been exploring the nanoparticle’s nanobio interface, that is, the composition of the nanoparticle’s protein corona.

The nanobio interface, scientists believe, may influence the outcome of a range of nanomedicine interventions. Scientists are particularly interested in understanding discrepancies that arise between nanoparticle performance in the laboratory and that in the clinic.

In their studies of the nanobio interface, scientists have evaluated potentially relevant factors, such as cell type, cell shape, and incubating temperature. Most recently, these studies have considered yet another factor—cell sex.

Investigators from Brigham and Women’s Hospital (BWH) and colleagues at Stanford University, McGill University, and University of California, Berkeley, have investigated whether differences between male versus female cells may influence how well cells uptake nanoparticles. The team has demonstrated that cell sex considerably influences cellular uptake of nanoparticles. Also, the team found that cells from men and women respond differently to reprogramming techniques used to enhance the ability of the cells to differentiate into a greater variety of cell types.

Detailed results appeared March 14 in the journal ACS Nano, in an article entitled “Effect of Cell Sex on Uptake of Nanoparticles: The Overlooked Factor at the Nanobio Interface.” The article presents results that may advance the development of safer and more effective nanomedicine applications that take sex into account.

“We demonstrate that cell sex leads to differences in NP [nanoparticle] uptake between male and female human amniotic stem cells (hAMSCs), with greater uptake by female cells,” the article’s authors indicated. “The experiments were replicated with primary fibroblasts isolated from the salivary gland of adult male and female donors of similar ages, and again the extent of NP uptake was altered by cell sex.

“However, in contrast to hAMSCs, uptake was greater in male cells. We also found out that female versus male amniotic stem cells exhibited different responses to reprogramming into induced pluripotent stem cells (iPSCs) by the Yamanaka factors.”

In the body, cells are awash in a wide range of biomolecules, including paracrine factors, which are small proteins that can interact with the surface of nanoparticles. The team found that paracrine factors varied between male and female cells. Of the 63 paracrine factors measured, 14 showed major differences. These differences can affect the biological identity of nanoparticles and thus alter their interaction with the cells.

Aside from the variation of paracrine factors between male and female cells, the team also found important differences in organization, distribution, and morphology of actin filaments in male and female hAMSCs. These filaments act like tiny tendrils that wrap around particles and engulf them.

“These differences could have a critical impact on the administration of nanoparticles,” said co-corresponding author Morteza Mahmoudi, Ph.D., an instructor in the Center for Nanomedicine and Department of Anesthesiology at BWH. “If nanoparticles are carrying a drug to deliver, different uptake could mean different therapeutic efficacy and other important differences, such as safety, in clinical data.”

hAMSCs can be coaxed into an even more robust stem cell state using a Sendai virus to deliver key factors to the nucleus. This reprogramming technique is quite common in stem cell biology—but the research team found that even this approach is affected by differences between male and female cells, with female cells responding at a nine-fold higher rate than male cells.

The team also tested nanoparticle absorption for other kinds of human cells, including fibroblasts from donors of older ages, and found significant differences. Interestingly, the team found that male fibroblast cells had higher levels of uptake than female fibroblast cells. They also saw differences in the shape of the cells’ mitochondria and endoplasmic reticulum structure, among other differences.

“What we’re seeing is that cell type is also going to be critical. If we’re trying to deliver a chemotherapeutic drug, the cell type we are targeting as well as the sex of the patient may influence how well the drug is delivered and absorbed,” noted Dr. Mahmoudi. “Further research is required on a greater variety of cell types and their intracellular differences to achieve more in-depth information on the physicochemical and mechanical differences between male versus female cells. We hope that our work helps the nanobio field understand and overcome some of the key challenges in drug delivery, ultimately providing better therapies for patients in a safer and highly effective sex-specific manner.”