Nanomaterials in diagnostics, imaging and delivery: Applications from COVID-19 to cancer

Abstract

Abstract: In the past two decades, the emergence of nanomaterials for biomedical applications has shown tremendous promise for changing the paradigm of all aspects of disease management. Nanomaterials are particularly attractive for being a modularly tunable system; with the ability to add functionality for early diagnostics, drug delivery, therapy, treatment and monitoring of patient response. In this review, a survey of the landscape of different classes of nanomaterials being developed for applications in diagnostics and imaging, as well as for the delivery of prophylactic vaccines and therapeutics such as small molecules and biologic drugs is undertaken; with a particular focus on COVID-19 diagnostics and vaccination. Work involving bio-templated nanomaterials for high-resolution imaging applications for early cancer detection, as well as for optimal cancer treatment efficacy, is discussed. The main challenges which need to be overcome from the standpoint of effective delivery and mitigating toxicity concerns are investigated. Subsequently, a section is included with resources for researchers and practitioners in nanomedicine, to help tailor their designs and formulations from a clinical perspective. Finally, three key areas for researchers to focus on are highlighted; to accelerate the development and clinical translation of these nanomaterials, thereby unleashing the true potential of nanomedicine in healthcare.

Keywords: Biological; Biomedical; COVID-19; Nanoscale; Nanostructure.

Figure 1

What is nanomedicine? A comparison of the different size scales, and a timeline of progress in the field. (a, b) Examples of structures in the human body: (a) a strand of human hair $\sim 10$–30 μm in diameter, (b) a red blood cell $\sim 3$–5 μm in size. Nanoscale materials range in size $\sim 1/10000\text{th}$–$1/100\text{th}$ of the thickness of a human hair. (c–e) Carbon-based nanomaterials: (c) 0D graphene dot $\sim 0.7$ nm, (d) 1D carbon nanotube $\sim 1$–2 nm in diameter, and (e) 2D sheet of graphene is $\sim 0.35$ nm in thickness. (f) A helix of double-stranded DNA is $\sim 2$–12 nm across. (g, h) Inorganic nanoparticles, such as: (g) quantum dots $\sim 1$–5 nm, while (h) gold nanoparticles $\sim 5$–100 nm in size. (i) The SARS-CoV-2 virus, responsible for the global COVID-19 pandemic, is $\sim 60$–140 nm in diameter. (j) In comparison, typical lipid nanoparticle formulations for the mRNA vaccines against COVID-19 are $\sim 50$–150 nm. Created with Biorender.com. (k) Accelerated rate of clinical progress in nanomedicine, since 2016. Data adapted from Anselmo and Mitragotri.^[–5]

Figure 2

Working demonstrations of nanomaterials for rapid testing in COVID-19: (a) A PCR-free, rapid test ($<2$ min) developed using PMO oligos on Au nanoparticle-decorated graphene field-effect transistor (g-FET), with a distinct signal response (b) in COVID-19 infected patients, compared to healthy individuals. Reprinted (adapted) with permission from Li et al.^[30] ©2021 Elsevier. (c) Antibody-free nanosensor, using PEG—phospholipid polymers adsorbed onto single-walled carbon nanotubes (CNTs). (d) The fluorescence spectrum of CNTs is used to identify the presence of the N-protein of the SARS-CoV-2 virus. Reprinted (adapted) from MIT News, and with permission from Cho et al.^[26] ©2021 American Chemical Society. (e) CNT-FET nanosensor, on a flexible printed circuit, for rapid detection of the SARS-CoV-2 RdRP gene, at a range of concentrations (f) down to 10 fM. Reprinted (adapted) with permission from Thanihaichelvan et al.^[27] CC BY-NC-ND 4.0. (g) A pooled, rapid testing ($\sim 74$s) framework for accurate, population-level screening of COVID-19 with high testing efficiency, using a triple-probe tetrahedral DNA framework on a g-FET. Reprinted (adapted) with permission from Wu et al.^[32] ©2022 American Chemical Society.

Figure 3

Fine tuning the nanomaterial formulations for successful delivery of mRNA-based COVID-19 vaccines: (a) Lipid nanoparticles protect the mRNA from environmental degradation factors, and during storage. Reproduced (adapted) from: Schoenmaker et al.^[46] CC BY 4.0. (b) The modified structure of the mRNA in both the Pfizer-BioNTech and Moderna vaccines, with all uridines replaced by N1-methylpseudouridine (m1$\mathrm{\Psi }$) to reduce innate immune responses and increase its stability. Reproduced (adapted) from: Heinz and Stiasny^[47] CC BY 4.0. (c) The fastest global large-scale rollout of the COVID-19 vaccines; relative to all other vaccines in history. Reproduced (adapted) from: Glassman et al.^[42] CC BY-NC 4.0. (d, e) Structures of the lipids used in the LNP formulations of the (d) Moderna and (e) Pfizer-BioNTech COVID-19 vaccines.

Figure 4

Designing nanomaterials for cancer diagnostics: (a) A “bio-templated” nanoprobe, M13 bacteriophage (in red) used to deliver a payload of interest such as dye molecules (purple), or a carbon nanotube (green), using antibody targeting. Shown here is an implementation to image an intramuscular mouse model of bacterial infection (glowing red spot on the right flank). Reprinted (adapted) from Bardhan et al.^[52] (b) A microfluidic-free, planar device created on treated graphene oxide (GO) nanosheet substrates, for quick and efficient capture of cells from whole blood; with enhanced capture efficiency from $\sim 54\%$ to $\sim 92\%$ using a mild thermal annealing process. Reprinted (adapted) from Bardhan et al.^[55] ©2017 American Chemical Society. (c) A “smart” activity-based nanosensor, developed as a non-invasive urine-based diagnostic for lung cancer. Upon delivery to the lungs, the reporter molecules get cleaved by tumor-associated proteases and excreted in the urine. Reprinted from MIT News, content from Kirkpatrick et al.^[56] ©2020 The American Association for the Advancement of Science. (d) Example of an application of a nanotemplate for plasmonic fluorescence enhancement: with dye molecules and Ag nanoparticles decorated on M13 phage, up to $\sim 24\times$ enhancement can be achieved. Reprinted (adapted) with permission from Huang et al.^[53] ©2019 John Wiley and Sons.

Figure 5

Nanomaterials for cancer therapeutics and tissue engineering: (a) A layer-by-layer (LbL) nanoparticle, around a PLGA core, with dual targeting capability for precision delivery of siRNA therapeutics in difficult-to-target cancers such as blood cancer. Reprinted (adapted) with permission from Choi et al.^[66] ©2019 John Wiley and Sons. (b–d) Schematic of (b) PEO-b-PCL nanoparticles (yellow), encapsulating an organic dye, DiR (red) and rare earth lanthanide nanoparticles (LNPs, blue). (c) NIR-II fluorescence of the LNPs revealed the best tumor distribution; confirmed by (d) confocal microscopy, showing co-localization of the LNPs (blue), tumor environment (red) and macrophages (green). Scale bar: $300\mathrm{\mu }$m. Reprinted (adapted) with permission from Tao et al.^[69] ©2017 Elsevier Ltd. (e–g) Plasmon-enhanced SWIR imaging probe: (e) Au nanorods, LbL-coated with polyelectrolyte, and folic acid-targeting; enabling (f) clear tumor distribution visualized in a mouse model of ovarian cancer. (g) Ex vivo harvested organs: strong co-localization with the bioluminescence signal from the tumor cells (T). Reprinted (adapted) with permission from Huang et al.^[70] ©2021 John Wiley and Sons. (h) MeGC-MMT nanocomposite hydrogel materials for bone tissue engineering. Comparing in vivo bone regeneration at 6 weeks post surgery in (i) blank (untreated) defects, with very little regeneration $\sim 10\%$, or (j) defects treated with MeGC$+1.5\%$MMT showed $\sim 69\%$ bone growth area. Scale bar: 1 mm. Reprinted (adapted) from Cui et al.^[71] CC BY 4.0.

Figure 6

Focus areas for the rapid development of Nanomedicine. (a) Expanding the role of AI/ML-based techniques in nanomaterial formulation; (b) establishing a set of industry standards and robust protocols to ensure purity and reproducibility; and (c) Achieving processes to scale-up nanomedicine formulations in accordance with regulatory practices to enable targeted, precision medicine for personalized therapy. Created with Biorender.com