Managing diabetes with nanomedicine: challenges and opportunities

KEY POINTS * Nanotechnology holds significant potential for improving the care of diabetes patients. * Nanoparticles are being developed as contrast agents to assist with the early diagnosis

of type 1 diabetes and several formulations have been successfully tested in pilot human clinical studies. * Nanotechnology tools are being used to generate implantable continuous glucose

monitoring sensors (CGMS) that enable more accurate and patient-friendly real-time tracking of blood glucose levels. * To improve the efficacy of insulin therapy, glucose responsive

nanoparticles are being developed to better mimic the physiological needs of the body for insulin. * Nanotechnology is being used to help engineer more effective vaccines for type 1 diabetes

in the hope of producing a cure. * This Review provides an analysis of the current state of nanotechnology-based approaches to improve the care of diabetes. ABSTRACT Nanotechnology-based

approaches hold substantial potential for improving the care of patients with diabetes. Nanoparticles are being developed as imaging contrast agents to assist in the early diagnosis of type

1 diabetes. Glucose nanosensors are being incorporated in implantable devices that enable more accurate and patient-friendly real-time tracking of blood glucose levels, and are also

providing the basis for glucose-responsive nanoparticles that better mimic the body's physiological needs for insulin. Finally, nanotechnology is being used in non-invasive approaches

to insulin delivery and to engineer more effective vaccine, cell and gene therapies for type 1 diabetes. Here, we analyse the current state of these approaches and discuss key issues for

their translation to clinical practice. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through

your institution Subscribe to this journal Receive 12 print issues and online access $209.00 per year only $17.42 per issue Learn more Buy this article * Purchase on SpringerLink * Instant

access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions *

Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS UTILITY AND PRECISION EVIDENCE OF TECHNOLOGY IN THE TREATMENT OF TYPE 1 DIABETES: A SYSTEMATIC REVIEW Article

Open access 05 October 2023 100 YEARS OF INSULIN: CELEBRATING THE PAST, PRESENT AND FUTURE OF DIABETES THERAPY Article 15 July 2021 ORAL NANOTHERAPEUTIC FORMULATION OF INSULIN WITH REDUCED

EPISODES OF HYPOGLYCAEMIA Article Open access 02 January 2024 REFERENCES * American Diabetes Association. Standards of medical care in diabetes — 2014. _Diabetes Care_ 37, S14–S80 (2014). *

Shaw, J. E., Sicree, R. A. & Zimmet, P. Z. Global estimates of the prevalence of diabetes for 2010 and 2030. _Diabetes Res. Clin. Pract._ 87, 4–14 (2010). Article  CAS  PubMed  Google

Scholar  * Zhang, P. et al. Global healthcare expenditure on diabetes for 2010 and 2030. _Diabetes Res. Clin. Pract._ 87, 293–301 (2010). Article  PubMed  Google Scholar  * Dabelea, D. The

accelerating epidemic of childhood diabetes. _Lancet_ 373, 1999–2000 (2009). Article  PubMed  Google Scholar  * Lieberman, S. M. & DiLorenzo, T. P. A comprehensive guide to antibody and

T-cell responses in type 1 diabetes. _Tissue Antigens_ 62, 359–377 (2003). Article  CAS  PubMed  Google Scholar  * Ismail-Beigi, F. Glycemic management of type 2 diabetes mellitus. _N. Engl.

J. Med._ 366, 1319–1327 (2012). Article  CAS  PubMed  Google Scholar  * Donath, M. Y. & Shoelson, S. E. Type 2 diabetes as an inflammatory disease. _Nature Rev. Immunol._ 11, 98–107

(2011). Article  CAS  Google Scholar  * Pickup, J. C. Management of diabetes mellitus: is the pump mightier than the pen? _Nature Rev. Endocrinol._ 8, 425–433 (2012). EXCELLENT REVIEW

COMPARING AND CONTRASTING THE CLINICAL BENEFITS FOR THE USE OF INSULIN PUMPS VERSUS INJECTABLE INSULIN FORMULATIONS. Article  CAS  Google Scholar  * American Diabetes Association. Standards

of medical care in diabetes—2013. _Diabetes Care_ 36 (Suppl. 1), 11–66 (2013). * Sarwar, N. et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a

collaborative meta-analysis of 102 prospective studies. _Lancet_ 375, 2215–2222 (2010). Article  CAS  PubMed  Google Scholar  * Schulman, R. C. et al. Association of glycemic control

parameters with clinical outcomes in chronic critical illness. _Endocr. Pract._ 20, 884–893 (2014). Article  PubMed  Google Scholar  * Berenson, D. F., Weiss, A. R., Wan, Z. L. & Weiss,

M. A. Insulin analogs for the treatment of diabetes mellitus: therapeutic applications of protein engineering. _Ann. NY Acad. Sci._ 1243, E40–E54 (2011). Article  PubMed  Google Scholar  *

Tamborlane, W. V. et al. Continuous glucose monitoring and intensive treatment of type 1 diabetes. _N. Engl. J. Med._ 359, 1464–1476 (2008). Article  PubMed  Google Scholar  * Heinemann, L.

New ways of insulin delivery. _Int. J. Clin. Pract._ 65 (Suppl. 170), 31–46 (2011). EXCELLENT REVIEW SUMMARIZING THE ADVANCES TOWARDS DEVELOPING INSULIN ANALOGUES WITH TAILORED

PHARMACOKINETICS. Article  Google Scholar  * Pickup, J. C. Insulin-pump therapy for type 1 diabetes mellitus. _N. Engl. J. Med._ 366, 1616–1624 (2012). Article  CAS  PubMed  Google Scholar 

* Russell, S. J. et al. Outpatient glycemic control with a bionic pancreas in type 1 diabetes. _N. Engl. J. Med._ 371, 313–325 (2014). A PHASE II CLINICAL TRIAL THAT DEMONSTRATES THE

IMPROVED EFFICACY AND SAFETY OF A WEARABLE, AUTOMATED, BIHORMONAL, BIONIC PANCREAS DUAL HORMONE INSULIN PUMP COMPARED TO A CONVENTIONAL INSULIN PUMP. Article  PubMed  PubMed Central  CAS 

Google Scholar  * Resnick, H. E., Foster, G. L., Bardsley, J. & Ratner, R. E. Achievement of American Diabetes Association clinical practice recommendations among US adults with

diabetes, 1999–2002: the National Health and Nutrition Examination Survey. _Diabetes Care_ 29, 531–537 (2006). Article  PubMed  Google Scholar  * Owens, D. R. New horizons — alternative

routes for insulin therapy. _Nature Rev. Drug Discov._ 1, 529–540 (2002). Article  CAS  Google Scholar  * Mehanna, A. Antidiabetic agents: past, present and future. _Future Med. Chem._ 5,

411–430 (2013). Article  CAS  PubMed  Google Scholar  * Weissleder, R. & Pittet, M. J. Imaging in the era of molecular oncology. _Nature_ 452, 580–589 (2008). Article  CAS  PubMed 

PubMed Central  Google Scholar  * Whitesides, G. M. The 'right' size in nanobiotechnology. _Nature Biotech._ 21, 1161–1165 (2003). Article  CAS  Google Scholar  * Dvir, T., Timko,

B. P., Kohane, D. S. & Langer, R. Nanotechnological strategies for engineering complex tissues. _Nature Nanotech._ 6, 13–22 (2011). Article  CAS  Google Scholar  * Schroeder, A. et al.

Treating metastatic cancer with nanotechnology. _Nature Rev. Cancer_ 12, 39–50 (2012). Article  CAS  Google Scholar  * LaVan, D. A., Lynn, D. M. & Langer, R. Moving smaller in drug

discovery and delivery. _Nature Rev. Drug Discov._ 1, 77–84 (2002). Article  CAS  Google Scholar  * McNeil, S. E. Unique benefits of nanotechnology to drug delivery and diagnostics. _Methods

Mol. Biol._ 697, 3–8 (2011). Article  CAS  PubMed  Google Scholar  * Venkatraman, S. S., Ma, L. L., Natarajan, J. V. & Chattopadhyay, S. Polymer- and liposome-based nanoparticles in

targeted drug delivery. _Front. Biosci._ 2, 801–814 (2010). Article  Google Scholar  * Stinchcombe, T. E. Nanoparticle albumin-bound paclitaxel: a novel Cremphor-EL-free formulation of

paclitaxel. _Nanomed._ 2, 415–423 (2007). Article  CAS  Google Scholar  * Barbas, A. S., Mi, J., Clary, B. M. & White, R. R. Aptamer applications for targeted cancer therapy. _Future

Oncol._ 6, 1117–1126 (2010). Article  CAS  PubMed  Google Scholar  * Chiu, G. N. et al. Lipid-based nanoparticulate systems for the delivery of anti-cancer drug cocktails: Implications on

pharmacokinetics and drug toxicities. _Curr. Drug Metab._ 10, 861–874 (2009). Article  CAS  PubMed  Google Scholar  * Schroeder, A., Levins, C. G., Cortez, C., Langer, R. & Anderson, D.

G. Lipid-based nanotherapeutics for siRNA delivery. _J. Intern. Med._ 267, 9–21 (2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Veiseh, O., Gunn, J. W. & Zhang, M. Design

and fabrication of magnetic nanoparticles for targeted drug delivery and imaging. _Adv. Drug Deliv. Rev._ 62, 284–304 (2010). Article  CAS  PubMed  Google Scholar  * Boisselier, E. &

Astruc, D. Gold nanoparticles in nanomedicine: preparations, imaging, diagnostics, therapies and toxicity. _Chem. Soc. Rev._ 38, 1759–1782 (2009). Article  CAS  PubMed  Google Scholar  *

Leonard, F. & Talin, A. A. Electrical contacts to one- and two-dimensional nanomaterials. _Nature Nanotech._ 6, 773–783 (2011). Article  CAS  Google Scholar  * Pickup, J. C., Zhi, Z. L.,

Khan, F., Saxl, T. & Birch, D. J. Nanomedicine and its potential in diabetes research and practice. _Diabetes Metab. Res. Rev._ 24, 604–610 (2008). Article  CAS  PubMed  Google Scholar

  * Naesens, M. & Sarwal, M. M. Molecular diagnostics in transplantation. _Nature Rev. Nephrol._ 6, 614–628 (2010). EXCELLENT REVIEW HIGHLIGHTING THE USE OF MOLECULAR IMAGING TOOLS TO

MONITOR CELL TRANSPLANTATION OUTCOMES. Article  CAS  Google Scholar  * Matveyenko, A. V. & Butler, P. C. Relationship between β-cell mass and diabetes onset. _Diabetes Obes. Metab._ 10

(Suppl. 4), 23–31 (2008). Article  CAS  PubMed  PubMed Central  Google Scholar  * Reiner, T. et al. Accurate measurement of pancreatic islet β-cell mass using a second-generation fluorescent

exendin-4 analog. _Proc. Natl Acad. Sci. USA_ 108, 12815–12820 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Moore, A., Bonner-Weir, S. & Weissleder, R. Noninvasive

_in vivo_ measurement of β-cell mass in mouse model of diabetes. _Diabetes_ 50, 2231–2236 (2001). Article  CAS  PubMed  Google Scholar  * Malaisse, W. J. & Maedler, K. Imaging of the

β-cells of the islets of Langerhans. _Diabetes Res. Clin. Pract._ 98, 11–18 (2012). Article  CAS  PubMed  Google Scholar  * Lamprianou, S. et al. High-resolution magnetic resonance imaging

quantitatively detects individual pancreatic islets. _Diabetes_ 60, 2853–2860 (2011). Article  PubMed  PubMed Central  CAS  Google Scholar  * Leibiger, I. B., Caicedo, A. & Berggren, P.

O. Non-invasive _in vivo_ imaging of pancreatic β-cell function and survival — a perspective. _Acta Physiol._ 204, 178–185 (2012). Article  CAS  Google Scholar  * Fu, W., Wojtkiewicz, G.,

Weissleder, R., Benoist, C. & Mathis, D. Early window of diabetes determinism in NOD mice, dependent on the complement receptor CRIg, identified by noninvasive imaging. _Nature Immunol._

13, 361–368 (2012). Article  CAS  Google Scholar  * Li, D. et al. Imaging dynamic insulin release using a fluorescent zinc indicator for monitoring induced exocytotic release (ZIMIR).

_Proc. Natl Acad. Sci. USA_ 108, 21063–21068 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Lee, N. et al. Magnetosome-like ferrimagnetic iron oxide nanocubes for highly

sensitive MRI of single cells and transplanted pancreatic islets. _Proc. Natl Acad. Sci. USA_ 108, 2662–2667 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Medarova, Z.,

Evgenov, N. V., Dai, G., Bonner-Weir, S. & Moore, A. _In vivo_ multimodal imaging of transplanted pancreatic islets. _Nature Protoc._ 1, 429–435 (2006). Article  CAS  Google Scholar  *

Medarova, Z. & Moore, A. MRI as a tool to monitor islet transplantation. _Nature Rev. Endocrinol._ 5, 444–452 (2009). Article  Google Scholar  * Andralojc, K. et al. Obstacles on the way

to the clinical visualisation of β cells: looking for the Aeneas of molecular imaging to navigate between Scylla and Charybdis. _Diabetologia_ 55, 1247–1257 (2012). Article  CAS  PubMed 

PubMed Central  Google Scholar  * Wu, Z. & Kandeel, F. Radionuclide probes for molecular imaging of pancreatic β-cells. _Adv. Drug Delivery Rev._ 62, 1125–1138 (2010). Article  CAS 

Google Scholar  * Sun, C., Lee, J. S. & Zhang, M. Magnetic nanoparticles in MR imaging and drug delivery. _Adv. Drug Delivery Rev._ 60, 1252–1265 (2008). Article  CAS  Google Scholar  *

Gaglia, J. L. et al. Noninvasive imaging of pancreatic islet inflammation in type 1A diabetes patients. _J. Clin. Invest._ 121, 442–445 (2011). CLINICAL STUDY THAT DEMONSTRATES FEASIBILITY

OF USING FERUMOXTRAN-10 — A DEXTRAN-COATED IRON OXIDE NANOPARTICLE TO MONITOR PANCREATITIS. Article  CAS  PubMed  Google Scholar  * Mauras, N., Fox, L., Englert, K. & Beck, R. W.

Continuous glucose monitoring in type 1 diabetes. _Endocr._ 43, 41–50 (2013). Article  CAS  Google Scholar  * Bernhardt, P. Self-monitoring blood glucose test systems for over-the-counter

use. _U.S. Food and Drug Administration_ [online] * Scognamiglio, V. Nanotechnology in glucose monitoring: advances and challenges in the last 10 years. _Biosens. Bioelectron._ 47C, 12–25

(2013). Article  CAS  Google Scholar  * Ansari, S. G. et al. Glucose sensor based on nano-baskets of tin oxide templated in porous alumina by plasma enhanced CVD. _Biosens. Bioelectron._ 23,

1838–1842 (2008). Article  CAS  PubMed  Google Scholar  * Bankar, S. B., Bule, M. V., Singhal, R. S. & Ananthanarayan, L. Glucose oxidase — an overview. _Biotechnol. Adv._ 27, 489–501

(2009). Article  CAS  PubMed  Google Scholar  * Ricci, F. et al. Novel planar glucose biosensors for continuous monitoring use. _Biosens. Bioelectron._ 20, 1993–2000 (2005). Article  CAS 

PubMed  Google Scholar  * Zhang, S., Wang, N., Yu, H., Niu, Y. & Sun, C. Covalent attachment of glucose oxidase to an Au electrode modified with gold nanoparticles for use as glucose

biosensor. _Bioelectrochemistry_ 67, 15–22 (2005). Article  CAS  PubMed  Google Scholar  * Tang, H. et al. Amperometric glucose biosensor based on adsorption of glucose oxidase at platinum

nanoparticle-modified carbon nanotube electrode. _Anal. Biochem._ 331, 89–97 (2004). Article  CAS  PubMed  Google Scholar  * Claussen, J. C. et al. Electrochemical glucose biosensor of

platinum nanospheres connected by carbon nanotubes. _J. Diabetes Sci. Technol._ 4, 312–319 (2010). Article  PubMed  PubMed Central  Google Scholar  * Hoedemaekers, C. W., Klein Gunnewiek, J.

M., Prinsen, M. A., Willems, J. L. & Van der Hoeven, J. G. Accuracy of bedside glucose measurement from three glucometers in critically ill patients. _Crit. Care Med._ 36, 3062–3066

(2008). Article  CAS  PubMed  Google Scholar  * Hussain, A. M., Sarangi, S. N., Kesarwani, J. A. & Sahu, S. N. Au-nanocluster emission based glucose sensing. _Biosens. Bioelectron._ 29,

60–65 (2011). Article  CAS  PubMed  Google Scholar  * Jiang, L. C. & Zhang, W. D. A highly sensitive nonenzymatic glucose sensor based on CuO nanoparticles-modified carbon nanotube

electrode. _Biosens. Bioelectron._ 25, 1402–1407 (2010). Article  CAS  PubMed  Google Scholar  * Yang, Y. et al. Glucose sensors based on electrodeposition of molecularly imprinted polymeric

micelles: a novel strategy for MIP sensors. _Biosens. Bioelectron._ 26, 2607–2612 (2011). Article  CAS  PubMed  Google Scholar  * Yang, J., Jiang, L. C., Zhang, W. D. & Gunasekaran, S.

A highly sensitive non-enzymatic glucose sensor based on a simple two-step electrodeposition of cupric oxide (CuO) nanoparticles onto multi-walled carbon nanotube arrays. _Talanta_ 82, 25–33

(2010). Article  CAS  PubMed  Google Scholar  * Pickup, J. C., Hussain, F., Evans, N. D., Rolinski, O. J. & Birch, D. J. Fluorescence-based glucose sensors. _Biosens. Bioelectron._ 20,

2555–2565 (2005). Article  CAS  PubMed  Google Scholar  * Nielsen, J. K. et al. Clinical evaluation of a transcutaneous interrogated fluorescence lifetime-based microsensor for continuous

glucose reading. _J. Diabetes Sci. Technol._ 3, 98–109 (2009). Article  PubMed  PubMed Central  Google Scholar  * Schultz, J. S., Mansouri, S. & Goldstein, I. J. Affinity sensor: a new

technique for developing implantable sensors for glucose and other metabolites. _Diabetes Care_ 5, 245–253 (1982). Article  CAS  PubMed  Google Scholar  * Liao, K. C. et al. Percutaneous

fiber-optic sensor for chronic glucose monitoring _in vivo_. _Biosens. Bioelectron._ 23, 1458–1465 (2008). Article  CAS  PubMed  Google Scholar  * Chen, P. C., Wan, L. S., Ke, B. B. &

Xu, Z. K. Honeycomb-patterned film segregated with phenylboronic acid for glucose sensing. _Langmuir_ 27, 12597–12605 (2011). Article  CAS  PubMed  Google Scholar  * Kataoka, K., Hisamitsu,

I., Sayama, N., Okano, T. & Sakurai, Y. Novel sensing system for glucose based on the complex formation between phenylborate and fluorescent diol compounds. _J. Biochem._ 117, 1145–1147

(1995). Article  CAS  PubMed  Google Scholar  * Parmpi, P. & Kofinas, P. Biomimetic glucose recognition using molecularly imprinted polymer hydrogels. _Biomaterials_ 25, 1969–1973

(2004). Article  CAS  PubMed  Google Scholar  * Edelman, G. M. et al. The covalent and three-dimensional structure of concanavalin A. _Proc. Natl Acad. Sci. USA_ 69, 2580–2584 (1972).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Ge, X. et al. Comparing the performance of the optical glucose assay based on glucose binding protein with high-performance

anion-exchange chromatography with pulsed electrochemical detection: efforts to design a low-cost point-of-care glucose sensor. _J. Diabetes Sci. Technol._ 1, 864–872 (2007). Article  PubMed

  PubMed Central  Google Scholar  * Bull, S. D. et al. Exploiting the reversible covalent bonding of boronic acids: recognition, sensing, and assembly. _Accounts Chem. Res._ 46, 312–326

(2013). Article  CAS  Google Scholar  * Barone, P. W. & Strano, M. S. Single walled carbon nanotubes as reporters for the optical detection of glucose. _J. Diabetes Sci. Technol._ 3,

242–252 (2009). Article  PubMed  PubMed Central  Google Scholar  * Yum, K., McNicholas, T. P., Mu, B. & Strano, M. S. Single-walled carbon nanotube-based near-infrared optical glucose

sensors toward _in vivo_ continuous glucose monitoring. _J. Diabetes Sci. Technol._ 7, 72–87 (2013). Article  PubMed  PubMed Central  Google Scholar  * Balaconis, M. K., Billingsley, K.,

Dubach, M. J., Cash, K. J. & Clark, H. A. The design and development of fluorescent nano-optodes for _in vivo_ glucose monitoring. _J. Diabetes Sci. Technol._ 5, 68–75 (2011). Article 

PubMed  PubMed Central  Google Scholar  * Billingsley, K. et al. Fluorescent nano-optodes for glucose detection. _Anal. Chem._ 82, 3707–3713 (2010). Article  CAS  PubMed  PubMed Central 

Google Scholar  * Klonoff, D. C. Overview of fluorescence glucose sensing: a technology with a bright future. _J. Diabetes Sci. Technol._ 6, 1242–1250 (2012). Article  PubMed  PubMed Central

  Google Scholar  * Barone, P. W., Baik, S., Heller, D. A. & Strano, M. S. Near-infrared optical sensors based on single-walled carbon nanotubes. _Nature Mater._ 4, 86–92 (2005). Article

  CAS  Google Scholar  * Barone, P. W., Parker, R. S. & Strano, M. S. _In vivo_ fluorescence detection of glucose using a single-walled carbon nanotube optical sensor: design,

fluorophore properties, advantages, and disadvantages. _Anal. Chem._ 77, 7556–7562 (2005). Article  CAS  PubMed  Google Scholar  * Iverson, N. M. et al. _In vivo_ biosensing via

tissue-localizable near-infrared-fluorescent single-walled carbon nanotubes. _Nature Nanotech._ 8, 873–880 (2013). Article  CAS  Google Scholar  * Saito, N. et al. Safe clinical use of

carbon nanotubes as innovative biomaterials. _Chem. Rev._ 114, 6040–6079 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  * Schipper, M. L. et al. A pilot toxicology study of

single-walled carbon nanotubes in a small sample of mice. _Nature Nanotech._ 3, 216–221 (2008). Article  CAS  Google Scholar  * Liu, Z. et al. Circulation and long-term fate of

functionalized, biocompatible single-walled carbon nanotubes in mice probed by Raman spectroscopy. _Proc. Natl Acad. Sci. USA_ 105, 1410–1415 (2008). Article  CAS  PubMed  PubMed Central 

Google Scholar  * Khalil, O. S. in _Glucose Sensing_ Vol. 11 (eds Geddes, C. D. & Lakowicz, J. R.) (Springer Science, 2006). Google Scholar  * Vashist, S. K. Non-invasive glucose

monitoring technology in diabetes management: a review. _Anal. Chim. Acta_ 750, 16–27 (2012). Article  CAS  PubMed  Google Scholar  * Krol, S., Ellis-Behnke, R. & Marchetti, P.

Nanomedicine for treatment of diabetes in an aging population: state-of-the-art and future developments. _Nanomed._ 8 (Suppl. 1), 69–76 (2012). Article  CAS  Google Scholar  * Zhi, Z. L.,

Khan, F. & Pickup, J. C. Multilayer nanoencapsulation: a nanomedicine technology for diabetes research and management. _Diabetes Res. Clin. Pract._ 100, 162–169 (2013). Article  PubMed 

Google Scholar  * Peng, Q., Zhang, Z. R., Gong, T., Chen, G. Q. & Sun, X. A rapid-acting, long-acting insulin formulation based on a phospholipid complex loaded PHBHHx nanoparticles.

_Biomaterials_ 33, 1583–1588 (2012). Article  CAS  PubMed  Google Scholar  * Brownlee, M. & Cerami, A. A glucose-controlled insulin-delivery system: semisynthetic insulin bound to

lectin. _Science_ 206, 1190–1191 (1979). FIRST EXAMPLE OF A GLUCOSE-RESPONSIVE INSULIN FORMULATION. Article  CAS  PubMed  Google Scholar  * Zhao, Y., Trewyn, B. G., Slowing, I. I. & Lin,

V. S. Mesoporous silica nanoparticle-based double drug delivery system for glucose-responsive controlled release of insulin and cyclic AMP. _J. Am. Chem. Soc._ 131, 8398–8400 (2009).

Article  CAS  PubMed  Google Scholar  * Ensign, L. M., Cone, R. & Hanes, J. Oral drug delivery with polymeric nanoparticles: the gastrointestinal mucus barriers. _Adv. Drug Deliv. Rev._

64, 557–570 (2012). Article  CAS  PubMed  Google Scholar  * Pegoraro, C., Macneil, S. & Battaglia, G. Transdermal drug delivery: from micro to nano. _Nanoscale_ 4, 1881–1894 (2012).

Article  CAS  PubMed  Google Scholar  * McMahon, G. T. & Arky, R. A. Inhaled insulin for diabetes mellitus. _M. Engl. J. Med._ 356, 497–502 (2007). Article  CAS  Google Scholar  *

Weidemaier, K. et al. Multi-day pre-clinical demonstration of glucose/galactose binding protein-based fiber optic sensor. _Biosens. Bioelectron._ 26, 4117–4123 (2011). Article  CAS  PubMed 

Google Scholar  * Sheridan, C. Proof of concept for next-generation nanoparticle drugs in humans. _Nature Biotech._ 30, 471–473 (2012). Article  CAS  Google Scholar  * Fleige, E., Quadir, M.

A. & Haag, R. Stimuli-responsive polymeric nanocarriers for the controlled transport of active compounds: concepts and applications. _Adv. Drug Delivery Rev._ 64, 866–884 (2012).

Article  CAS  Google Scholar  * Qiu, Y. & Park, K. Environment-sensitive hydrogels for drug delivery. _Adv. Drug Deliv. Rev._ 53, 321–339 (2001). Article  CAS  PubMed  Google Scholar  *

Stuart, M. A. et al. Emerging applications of stimuli-responsive polymer materials. _Nature Mater._ 9, 101–113 (2010). Article  CAS  Google Scholar  * Wu, W., Mitra, N., Yan, E. C. &

Zhou, S. Multifunctional hybrid nanogel for integration of optical glucose sensing and self-regulated insulin release at physiological pH. _ACS Nano_ 4, 4831–4839 (2010). Article  CAS 

PubMed  Google Scholar  * Ferri, S., Kojima, K. & Sode, K. Review of glucose oxidases and glucose dehydrogenases: a bird's eye view of glucose sensing enzymes. _J. Diabetes Sci.

Technol._ 5, 1068–1076 (2011). Article  PubMed  PubMed Central  Google Scholar  * Fischel-Ghodsian, F., Brown, L., Mathiowitz, E., Brandenburg, D. & Langer, R. Enzymatically controlled

drug delivery. _Proc. Natl Acad. Sci. USA_ 85, 2403–2406 (1988). Article  CAS  PubMed  PubMed Central  Google Scholar  * Gu, Z. et al. Glucose-responsive microgels integrated with enzyme

nanocapsules for closed-loop insulin delivery. _ACS Nano_ 7, 6758–6766 (2013). Article  CAS  PubMed  Google Scholar  * Luo, J. et al. Super long-term glycemic control in diabetic rats by

glucose-sensitive LbL films constructed of supramolecular insulin assembly. _Biomaterials_ 33, 8733–8742 (2012). Article  CAS  PubMed  Google Scholar  * Qi, W. et al. Triggered release of

insulin from glucose-sensitive enzyme multilayer shells. _Biomaterials_ 30, 2799–2806 (2009). Article  CAS  PubMed  Google Scholar  * Gu, Z. et al. Injectable nano-network for

glucose-mediated insulin delivery. _ACS Nano_ 7, 4194–4201 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Wu, W. & Zhou, S. Responsive materials for self-regulated

insulin delivery. _Macromolec. Biosci._ 13, 1464–1477 (2013). Article  CAS  Google Scholar  * Zion, T. C. _Glucose-responsive materials for self-regulated insulin delivery_. Thesis,

Massachusetts Institute of Technology (2004). Google Scholar  * Powell, A. E. & Leon, M. A. Reversible interaction of human lymphocytes with the mitogen concanavalin A. _Exp. Cell Res._

62, 315–325 (1970). Article  CAS  PubMed  Google Scholar  * Cartwright, H. A Review of deal making in 2010. 2011, 17 _PharmaDeals Review_ (2010). Google Scholar  * Schechter, A. H. &

Perlmutter, R. M. in _2014 Merk Investor Briefing Webcast_ (ed. Frazier, K.) (Merck & Co., 2014). Google Scholar  * Matsumoto, A. et al. A synthetic approach toward a self-regulated

insulin delivery system. _Angew. Chem. Int. Ed. Engl._ 51, 2124–2128 (2012). Article  CAS  PubMed  Google Scholar  * Wu, Q., Wang, L., Yu, H., Wang, J. & Chen, Z. Organization of

glucose-responsive systems and their properties. _Chem. Rev._ 111, 7855–7875 (2011). Article  CAS  PubMed  Google Scholar  * Bae, Y., Fukushima, S., Harada, A. & Kataoka, K. Design of

environment-sensitive supramolecular assemblies for intracellular drug delivery: polymeric micelles that are responsive to intracellular pH change. _Angewandte Chemie_ 42, 4640–4643 (2003).

Article  CAS  PubMed  Google Scholar  * Matsumoto, A., Yoshida, R. & Kataoka, K. Glucose-responsive polymer gel bearing phenylborate derivative as a glucose-sensing moiety operating at

the physiological pH. _Biomacromolecules_ 5, 1038–1045 (2004). Article  CAS  PubMed  Google Scholar  * Uchiyama, T., Kiritoshi, Y., Watanabe, J. & Ishihara, K. Degradation of

phospholipid polymer hydrogel by hydrogen peroxide aiming at insulin release device. _Biomaterials_ 24, 5183–5190 (2003). Article  CAS  PubMed  Google Scholar  * Korin, N. et al.

Shear-activated nanotherapeutics for drug targeting to obstructed blood vessels. _Science_ 337, 738–742 (2012). Article  CAS  PubMed  Google Scholar  * Yavuz, M.S. et al. Gold nanocages

covered by smart polymers for controlled release with near-infrared light. _Nature Mater._ 8, 935–939 (2009). Article  CAS  Google Scholar  * Stanley, S. A. et al. Radio-wave heating of iron

oxide nanoparticles can regulate plasma glucose in mice. _Science_ 336, 604–608 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  * Di, J. et al. Ultrasound-triggered regulation

of blood glucose levels using injectable nano-network. _Adv. Healthc. Mater._ 3, 811–816 (2014). Article  CAS  PubMed  Google Scholar  * Bakhru, S. H., Furtado, S., Morello, A. P. &

Mathiowitz, E. Oral delivery of proteins by biodegradable nanoparticles. _Adv. Drug Deliv. Rev._ 65, 811–821 (2013). Article  CAS  PubMed  Google Scholar  * Rabanel, J. M., Aoun, V., Elkin,

I., Mokhtar, M. & Hildgen, P. Drug-loaded nanocarriers: passive targeting and crossing of biological barriers. _Curr. Med. Chem._ 19, 3070–3102 (2012). Article  CAS  PubMed  Google

Scholar  * Jin, Y. et al. Goblet cell-targeting nanoparticles for oral insulin delivery and the influence of mucus on insulin transport. _Biomaterials_ 33, 1573–1582 (2012). Article  CAS 

PubMed  Google Scholar  * Sahay, G., Alakhova, D. Y. & Kabanov, A. V. Endocytosis of nanomedicines. _J. Control Release_ 145, 182–195 (2010). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Jepson, M. A., Clark, M. A. & Hirst, B. H. M cell targeting by lectins: a strategy for mucosal vaccination and drug delivery. _Adv. Drug Deliv. Rev._ 56, 511–525 (2004).

Article  CAS  PubMed  Google Scholar  * Sweet, D. M., Kolhatkar, R. B., Ray, A., Swaan, P. & Ghandehari, H. Transepithelial transport of PEGylated anionic poly(amidoamine) dendrimers:

implications for oral drug delivery. _J. Control Release_ 138, 78–85 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar  * Pridgen, E. M. et al. Transepithelial transport of

fc-targeted nanoparticles by the neonatal fc receptor for oral delivery. _Sci. Transl. Med._ 5, 213ra167 (2013). Article  PubMed  PubMed Central  CAS  Google Scholar  * Edwards, D. A. et al.

Large porous particles for pulmonary drug delivery. _Science_ 276, 1868–1871 (1997). Article  CAS  PubMed  Google Scholar  * Patel, B., Gupta, V. & Ahsan, F. PEG–PLGA based large porous

particles for pulmonary delivery of a highly soluble drug, low molecular weight heparin. _J. Control Release_ 162, 310–320 (2012). Article  CAS  PubMed  Google Scholar  * Tang, B. C. et al.

Biodegradable polymer nanoparticles that rapidly penetrate the human mucus barrier. _Proc. Natl Acad. Sci. USA_ 106, 19268–19273 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar

  * Choi, H. S. et al. Rapid translocation of nanoparticles from the lung airspaces to the body. _Nature Biotech._ 28, 1300–1303 (2010). Article  CAS  Google Scholar  * Liu, J. et al. Solid

lipid nanoparticles for pulmonary delivery of insulin. _Int. J. Pharmaceut._ 356, 333–344 (2008). Article  CAS  Google Scholar  * Forst, T. et al. Time–action profile and patient assessment

of inhaled insulin via the Exubera device in comparison with subcutaneously injected insulin aspart via the FlexPen device. _Diabetes Technol. Ther._ 11, 87–92 (2009). Article  CAS  PubMed 

Google Scholar  * Hollander, P. A. et al. Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with type 2 diabetes: results of a 6-month,

randomized, comparative trial. _Diabetes Care_ 27, 2356–2362 (2004). PRESENTS RESULTS FROM A CLINICAL TRIAL DEMONSTRATING SAFETY AND EFFICACY OF THE INHALED INSULIN FORMULATION EXUBERA.

Article  CAS  PubMed  Google Scholar  * Mastrandrea, L. D. & Quattrin, T. Clinical evaluation of inhaled insulin. _Adv. Drug Deliv. Rev._ 58, 1061–1075 (2006). Article  CAS  PubMed 

Google Scholar  * Fischer, A. FDA approves Afrezza to treat diabetes. _FDA News Release_ [online] * Neumiller, J. J. & Campbell, R. K. Technosphere insulin: an inhaled prandial insulin

product. _BioDrugs_ 24, 165–172 (2010). Article  CAS  PubMed  Google Scholar  * Prausnitz, M. R. & Langer, R. Transdermal drug delivery. _Nature Biotech._ 26, 1261–1268 (2008). Article 

CAS  Google Scholar  * Nose, K., Pissuwan, D., Goto, M., Katayama, Y. & Niidome, T. Gold nanorods in an oil-base formulation for transdermal treatment of type 1 diabetes in mice.

_Nanoscale_ 4, 3776–3780 (2012). Article  CAS  PubMed  Google Scholar  * Choi, W. I. et al. Efficient skin permeation of soluble proteins via flexible and functional nano-carrier. _J.

Control Release_ 157, 272–278 (2012). Article  CAS  PubMed  Google Scholar  * Lopez, R. F., Seto, J. E., Blankschtein, D. & Langer, R. Enhancing the transdermal delivery of rigid

nanoparticles using the simultaneous application of ultrasound and sodium lauryl sulfate. _Biomaterials_ 32, 933–941 (2011). Article  CAS  PubMed  Google Scholar  * Higaki, M. et al.

Transdermal delivery of CaCO3-nanoparticles containing insulin. _Diabetes Technol. Ther._ 8, 369–374 (2006). Article  CAS  PubMed  Google Scholar  * Robertson, R. P. Islet transplantation as

a treatment for diabetes ‚ a work in progress. _N. Engl. J. Med._ 350, 694–705 (2004). EXCELLENT REVIEW PROVIDING A HISTORICAL PERSPECTIVE ON THE CHALLENGES AND OPPORTUNITIES FOR ISLET CELL

TRANSPLANTATION. Article  CAS  PubMed  Google Scholar  * Gates, R. J., Hunt, M. I., Smith, R. & Lazarus, N. R. Return to normal of blood–glucose, plasma–insulin, and weight gain in New

Zealand obese mice after implantation of islets of Langerhans. _Lancet_ 2, 567–570 (1972). FIRST DEMONSTRATION OF THE CONCEPT OF IMMUNOISOLATING PANCREATIC ISLET CELLS IN SEMIPERMEABLE

BARRIERS. Article  CAS  PubMed  Google Scholar  * Teramura, Y. & Iwata, H. Bioartificial pancreas microencapsulation and conformal coating of islet of Langerhans. _Adv. Drug Deliv. Rev._

62, 827–840 (2010). Article  CAS  PubMed  Google Scholar  * Lanza, R. P., Hayes, J. L. & Chick, W. L. Encapsulated cell technology. _Nature Biotech._ 14, 1107–1111 (1996). Article  CAS

  Google Scholar  * Wilson, J. T., Cui, W. & Chaikof, E. L. Layer-by-layer assembly of a conformal nanothin PEG coating for intraportal islet transplantation. _Nano Lett._ 8, 1940–1948

(2008). Article  CAS  PubMed  PubMed Central  Google Scholar  * Krol, S. et al. Multilayer nanoencapsulation. New approach for immune protection of human pancreatic islets. _Nano Lett._ 6,

1933–1939 (2006). Article  CAS  PubMed  Google Scholar  * Contreras, J. L. et al. A novel approach to xenotransplantation combining surface engineering and genetic modification of isolated

adult porcine islets. _Surgery_ 136, 537–547 (2004). Article  PubMed  Google Scholar  * Dolgin, E. Encapsulate this. _Nature Med._ 20, 9–11 (2014). Article  CAS  PubMed  Google Scholar  *

Buder, B., Alexander, M., Krishnan, R., Chapman, D. W. & Lakey, J. R. Encapsulated islet transplantation: strategies and clinical trials. _Immune Netw._ 13, 235–239 (2013). Article 

PubMed  PubMed Central  Google Scholar  * Czech, M. P., Aouadi, M. & Tesz, G. J. RNAi-based therapeutic strategies for metabolic disease. _Nature Rev. Endocrinol._ 7, 473–484 (2011).

Article  CAS  Google Scholar  * Li, F. & Mahato, R. I. RNA interference for improving the outcome of islet transplantation. _Adv. Drug Deliv. Rev._ 63, 47–68 (2011). Article  CAS  PubMed

  Google Scholar  * Ko, K. S., Lee, M., Koh, J. J. & Kim, S. W. Combined administration of plasmids encoding IL-4 and IL-10 prevents the development of autoimmune diabetes in nonobese

diabetic mice. _Mol. Ther._ 4, 313–316 (2001). Article  CAS  PubMed  Google Scholar  * Oh, S., Lee, M., Ko, K. S., Choi, S. & Kim, S. W. GLP-1 gene delivery for the treatment of type 2

diabetes. _Mol. Ther._ 7, 478–483 (2003). Article  CAS  PubMed  Google Scholar  * Moon, J. J., Huang, B. & Irvine, D. J. Engineering nano- and microparticles to tune immunity. _Adv.

Mater._ 24, 3724–3746 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  * Nochi, T. et al. Nanogel antigenic protein-delivery system for adjuvant-free intranasal vaccines.

_Nature Mater._ 9, 572–578 (2010). Article  CAS  Google Scholar  * Zhu, Q. et al. Large intestine-targeted, nanoparticle-releasing oral vaccine to control genitorectal viral infection.

_Nature Med._ 18, 1291–1296 (2012). Article  CAS  PubMed  Google Scholar  * Nembrini, C. et al. Nanoparticle conjugation of antigen enhances cytotoxic T-cell responses in pulmonary

vaccination. _Proc. Natl Acad. Sci. USA_ 108, E989–E997 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Kasturi, S. P. et al. Programming the magnitude and persistence of

antibody responses with innate immunity. _Nature_ 470, 543–547 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Geall, A. J. et al. Nonviral delivery of self-amplifying RNA

vaccines. _Proc. Natl Acad. Sci. USA_ 109, 14604–14609 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  * Nguyen, D. N. et al. Lipid-derived nanoparticles for immunostimulatory

RNA adjuvant delivery. _Proc. Natl Acad. Sci. USA_ 109, E797–E803 (2012). CAS  PubMed  PubMed Central  Google Scholar  * Tsai, S. et al. Reversal of autoimmunity by boosting memory-like

autoregulatory T cells. _Immunity_ 32, 568–580 (2010). NOTABLE STUDY DEMONSTRATING THE USE OF NANOPARTICLES TOWARDS DEVELOPING A DIABETES VACCINE. Article  CAS  PubMed  Google Scholar  *

Hrkach, J. et al. Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. _Sci. Transl. Med._ 4, 128ra39

(2012). Article  PubMed  Google Scholar  * Davis, M. E. et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. _Nature_ 464, 1067–1070 (2010).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Peer, D. et al. Nanocarriers as an emerging platform for cancer therapy. _Nature Nanotech._ 2, 751–760 (2007). Article  CAS  Google

Scholar  * Barenholz, Y. Doxil® — the first FDA-approved nano-drug: lessons learned. _J. Control Release_ 160, 117–134 (2012). A NOTABLE REVIEW HIGHLIGHTING THE DEVELOPMENT OF THE FIRST

FDA-APPROVED NANOPARTICLE-BASED THERAPEUTIC. Article  CAS  PubMed  Google Scholar  * Bertrand, N., Wu, J., Xu, X., Kamaly, N. & Farokhzad, O. C. Cancer nanotechnology: the impact of

passive and active targeting in the era of modern cancer biology. _Adv. Drug Deliv. Rev._ 66, 2–25 (2014). Article  CAS  PubMed  Google Scholar  * McCarthy, J. R. Nanomedicine and

cardiovascular disease. _Curr. Cardiovasc. Imag. Rep._ 3, 42–49 (2010). Article  Google Scholar  * Lobatto, M. E., Fuster, V., Fayad, Z. A. & Mulder, W. J. Perspectives and opportunities

for nanomedicine in the management of atherosclerosis. _Nature Rev. Drug Discov._ 10, 835–852 (2011). Article  CAS  Google Scholar  * Alam, S. R. et al. Ultrasmall superparamagnetic

particles of iron oxide in patients with acute myocardial infarction: early clinical experience. _Circ. Cardiovasc. Imag._ 5, 559–565 (2012). Article  Google Scholar  * Kim, B. Y. S., Rutka,

J. T. & Chan, W. C. W. Nanomedicine. _New Engl. J. Med._ 363, 2434–2443 (2010). Article  CAS  PubMed  Google Scholar  * Ventura, J. FDA issues guidance to support the responsible

development of nanotechnology products. _FDA News Release_ [online] FDA GUIDELINES TO HELP FOSTER THE SAFE DEVELOPMENT OF NANOTECHNOLOGY BASED PRODUCTS FOR CLINICAL USE. * Whitehead, K. A.,

Langer, R. & Anderson, D. G. Knocking down barriers: advances in siRNA delivery. _Nature Rev. Drug Discov._ 8, 129–138 (2009). Article  CAS  Google Scholar  * Yi, P., Park, J. S. &

Melton, D. A. Betatrophin: a hormone that controls pancreatic β cell proliferation. _Cell_ 153, 747–758 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Grunberger, G. The

need for better insulin therapy. _Diabetes Obes. Metab._ 15 (Suppl. 1), 1–5 (2013). Article  CAS  PubMed  Google Scholar  * Keenan, D. B., Mastrototaro, J. J., Voskanyan, G. & Steil, G.

M. Delays in minimally invasive continuous glucose monitoring devices: a review of current technology. _J. Diabetes Sci. Technol._ 3, 1207–1214 (2009). Article  PubMed  PubMed Central 

Google Scholar  * Hovorka, R. Closed-loop insulin delivery: from bench to clinical practice. _Nature Rev. Endocrinol._ 7, 385–395 (2011). Article  CAS  Google Scholar  * Hovorka, R., Nodale,

M., Haidar, A. & Wilinska, M. E. Assessing performance of closed-loop insulin delivery systems by continuous glucose monitoring: drawbacks and way forward. _Diabetes Technol. Ther._ 15,

4–12 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Schmid, C., Haug, C., Heinemann, L. & Freckmann, G. System accuracy of blood glucose monitoring systems: impact of

use by patients and ambient conditions. _Diabetes Technol. Ther._ 15, 889–896 (2013). Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS We thank M. Anderson for

helpful discussions and J. Gunn for his input towards the preparation of figure displays. Work in the author's laboratory was supported by the Leona M. and Harry B. Helmsley Charitable

Trust Foundation (Grant 09PG-T1D027), the Juvenile Diabetes Research Foundation (JDRF) (Grant 17-2007-1063), the US National Institutes of Health (Grants EB000244, EB000351, DE013023 and

CA151884) and a generous gift from the Tayebati Family Foundation. O.V. and B.C.T. were supported by the JDRF postdoctoral fellowships (Grants 3-2013-178 and 3-2011-310, respectively).

AUTHOR INFORMATION Author notes * Omid Veiseh and Benjamin C. Tang: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Department of Chemical Engineering,

Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, 02139, Massachusetts, USA Omid Veiseh, Daniel G. Anderson & Robert Langer * David H. Koch Institute for

Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, 02139, Massachusetts, USA Omid Veiseh, Benjamin C. Tang, Daniel G. Anderson & Robert

Langer * Department of Anesthesiology, Boston Children's Hospital, 300 Longwood Ave., Boston, 02115, Massachusetts, USA Omid Veiseh, Benjamin C. Tang, Daniel G. Anderson & Robert

Langer * Department of Chemical Engineering, Carnegie Mellon University, 5000 Forbes Ave., Pittsburgh, 15213, Pennsylvania, USA Kathryn A. Whitehead * Division of Health Science and

Technology, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA Daniel G. Anderson & Robert Langer * Institute for Medical Engineering and Science, Massachusetts

Institute of Technology, Cambridge, 02139, Massachusetts, USA Daniel G. Anderson & Robert Langer Authors * Omid Veiseh View author publications You can also search for this author

inPubMed Google Scholar * Benjamin C. Tang View author publications You can also search for this author inPubMed Google Scholar * Kathryn A. Whitehead View author publications You can also

search for this author inPubMed Google Scholar * Daniel G. Anderson View author publications You can also search for this author inPubMed Google Scholar * Robert Langer View author

publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Robert Langer. ETHICS DECLARATIONS COMPETING INTERESTS R.L. and D.G.A are

shareholders of and are recipient of research grants from several drug delivery, pharmaceuticals and biotechnology companies, including those whose technologies and products are discussed in

this article. The authors are inventors on several patents in the field of drug delivery/formulations that are owned by their current or former employers. The views presented here should

not be considered as endorsements of any specific product or company. POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3 POWERPOINT SLIDE

FOR FIG. 4 GLOSSARY * Hyperglycaemia A condition of high blood glucose levels, typically >200 mg/dL. * Insulin A peptide hormone that is produced by β-cells in the pancreas. It regulates

the metabolism of carbohydrates and fats and reduces blood glucose by promoting the absorption of glucose from blood to skeletal muscles and fat tissue. * β-cells Cells in the pancreas that

are located in the islets of Langerhans and that store and secrete insulin. * Hypoinsulinaemia A condition of abnormally low concentrations of insulin in the blood. * Hypoglycaemia A

condition of low blood glucose levels, typically <70 mg/dL. * Glucagon A peptide hormone that is produced by α-cells in the pancreas and raises blood glucose levels. * Open loop A form of

insulin replacement therapy whereby the required insulin levels are empirically estimated by blood glucose measurement and meal intake and insulin is injected by the patient at different

times throughout the day. * Magnetic resonance imaging (MRI). Imaging technique by which strong magnetic fields are applied to the area of interest, exciting hydrogen atoms to emit a radio

frequency signal, which is then captured. T1 (spin-lattice) and T2 (relaxation) processes can be captured to assess different types of tissue. * Inflammation Biological response of tissues

to harmful stimuli, such as foreign objects and dead cells. * Glucose oxidase An enzyme that catalyses the oxidation of glucose into hydrogen peroxide and D-glucono-δ-lactone. * Amperometric

Relating to the measurement of changes in electrical current of an electrode with an applied voltage in response to the presence of an analyte. * Carbon nanotubes Allotrope of carbon that

takes a cylindrical shape. * Voltammetric A subset of amperometry, where the applied voltage is additionally varied. * Phenylboronic acid (PBA). Mild Lewis acid that binds reversibly to 1,2-

and 1,3-diols, such as glucose. * Sol-gel crosslinker A reversible interaction that switches the properties of the bulk material from solution (sol) to a network (gel) phase. * PLGA

(poly(lactic-co-glycolic acid). A biodegradable copolymer used in a number of US Food and Drug Administration (FDA) approved therapeutic devices, including nanoparticles and sutures. *

Bioavailability The fraction of an administered dosage that reaches systemic circulation, where 100% is defined by intravenous injection. * Microfold cell (M cell). A cell that is found in

the epithelium of Peyer's patches in the intestines and that facilitates uptake of antigens. * Fc receptor Cell surface protein that is found on the surface of many cell types and

mediates binding of the Fc region of antibodies. * Interleukin Class of cytokines that are expressed by white blood cells and promote the development of T lymphocytes and B lymphocytes. *

Closed-loop A form of insulin replacement therapy whereby the required insulin is automatically determined and the proper insulin dosage is delivered with minimal patient involvement. RIGHTS

AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Veiseh, O., Tang, B., Whitehead, K. _et al._ Managing diabetes with nanomedicine: challenges and opportunities.

_Nat Rev Drug Discov_ 14, 45–57 (2015). https://doi.org/10.1038/nrd4477 Download citation * Published: 28 November 2014 * Issue Date: January 2015 * DOI: https://doi.org/10.1038/nrd4477

SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to

clipboard Provided by the Springer Nature SharedIt content-sharing initiative