ORAL DELIVERY OF BIOACTIVE PROTEIN MOLECULES: PROBLEMS AND PERSPECTIVES
Abstract and keywords
Abstract:
Bioactive peptides and proteins can be administered orally. However, this method remains largely ineffective because of enzymatic degradation in the gastrointestinal tract, the mucus layer, the selective epithelial barrier, the acidic stomach environment, and a short half-life. As a result, bioactive protein molecules have little prospect as functional food ingredients unless appropriate delivery systems are used. This review describes scientific trends and strategies aimed at solving the problem of the instability of peptides and proteins in the gastrointestinal tract during oral administration. The review analyzed scientific publications on the oral administration, stability, and bioavailability of peptides and proteins in the gastrointestinal tract registered in eLIBRARY.RU, MEDLINE, PubMed, EMBASE, Scopus, Web of Science, and Google Scholar between 2020 and 2025 (alongside some fundamental earlier works). Of the 1,346 manually selected publications, the review included 116 articles. Peptides can be encapsulated in solid lipid nanoparticles, nanostructured lipid carriers, liposomes, or polymer nanocarriers. Encapsulation increases stability and bioavailability during oral administration. Cell-penetrating peptides and their integration with various drug carriers create multifunctional delivery systems. Modified living biotherapeutic products are promising carriers for the targeted delivery of peptides and proteins. Novel methods include matrix protein amplification, protease inhibitors, permeability enhancers, chemical modification, and cyclization. The article also describes new cyclic biopeptides, a recombinant protein, and a native antiviral peptide with reliable bioactive properties. The maltodextrin-encapsulated antiviral peptide demonstrated a 1.8-fold increase in intestinal stability in vitro.

Keywords:
Peptides, proteins, oral delivery, cell-penetrating peptides, advanced microbial therapy, permeability enhancers, polymer systems, encapsulation, lipid carriers
Text
Text (PDF): Read Download
References

1. Wu J, Roesger S, Jones N, Hu C-MJ, Li SD. Cell-penetrating peptides for transmucosal delivery of proteins. Journal of Controlled Release. 2024;366:864–878. https://doi.org/10.1016/j.jconrel.2024.01.038

2. Pang H, Huang X, Xu ZP, Chen C, Han FY. Progress in oral insulin delivery by PLGA nanoparticles for the management of diabetes. Drug Discovery Today. 2023;28(1):103393. https://doi.org/10.1016/j.drudis.2022.103393

3. Wang YY, Li H, Rasool A, Wang HB, Manzoor R, et al. Polymeric nanoparticles (PNPs) for oral delivery of insulin. Journal of Nanobiotechnol. 2024;22(1):1. https://doi.org/10.1186/s12951-023-02253-y

4. Salama NN, Eddington ND, Fasano A. Tight junction modulation and its relationship to drug delivery. Advanced Drug Delivery Reviews. 2006;58(1):15–28. https://doi.org/10.1016/j.addr.2006.01.003

5. Zou J-J, Wei G, Xiong C, Yu Y, Li S, et al. Efficient oral insulin delivery enabled by transferrin-coated acid-resistant metal-organic framework nanoparticles. Science Advances. 2022;8(8):eabm4677. https://doi.org/10.1126/sciadv.abm4677

6. Zhu X, Shan W, Zhang P, Yun J, Shan G, et al. Penetratin derivative-based nanocomplexes for enhanced intestinal insulin delivery. Molecular Pharmaceutics. 2014;11(2):317–328. https://doi.org/10.1021/mp400493b

7. Smart AL, Gaisford S, Basit AW. Oral peptide and protein delivery: Intestinal obstacles and commercial prospects. Expert Opinion on Drug Delivery. 2014;11(8):1323–1335. https://doi.org/10.1517/17425247.2014.917077

8. Goldberg M, Gomez-Orellana I. Challenges for the oral delivery of macromolecules. Nature Reviews Drug Discovery. 2003;2(4):289–295. https://doi.org/10.1038/nrd1067

9. Drucker DJ. Advances in oral peptide therapeutics. Nature Reviews Drug Discovery. 2020;19(4):277–289. https://doi.org/10.1038/s41573-019-0053-0

10. Han Y, Gao Z, Chen L, Kang L, Huang W, et al. Multifunctional oral delivery systems for enhanced bioavailability of therapeutic peptides/proteins. Acta Pharmaceutica Sinica B. 2019;9(5):902–922. https://doi.org/10.1016/j.apsb.2019.01.004

11. Miao Y-B, Xu T, Gong Y, Chen A, Zou L, et al. Cracking the intestinal lymphatic system window utilizing oral delivery vehicles for precise therapy. Journal of Nanobiotechnology. 2023;21:263. https://doi.org/10.1186/s12951-023-01991-3

12. Dubey SK, Parab S, Dabholkar N, Singhvi G, Argrawal M, et al. Oral peptide delivery: Challenges and the way ahead. Drug Discovery Today. 2021;26(4):931–950. https://doi.org/10.1016/j.drudis.2021.01.001

13. Fallingborg J. Intraluminal pH of the human gastrointestinal tract. Danish Medical Bulletin. 1999;46(3):183–196. https://elibrary.ru/YCCJSX

14. Chen G, Kang W, Li W, Chen S, Gao Y. Oral delivery of protein and peptide drugs: From non-specific formulation approaches to intestinal cell targeting strategies. Theranostics. 2022;12(3):1419–1439. https://doi.org/10.7150/thno.61747

15. Buckley ST, Bækdal TA, Vegge A, Maarbjerg SJ, Knudsen LB, et al. Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist. Science Translational Medicine. 2018;10(467):eaar7047. https://doi.org/10.1126/scitranslmed.aar7047

16. Johansson MEV, Thomsson KA, Hansson GC. Proteomic analyses of the two mucus layers of the colon barrier reveal that their main component, the Muc2 mucin, is strongly bound to the Fcgbp protein. Journal of Proteome Research. 2009;8(7):3549–3557. https://doi.org/10.1021/pr9002504

17. Leon DL, Crouzier T, Sarkar A, Dunphy L, Han J, et al. Spatial configuration and composition of charge modulates transport into a mucin hydrogel barrier. Biophysical Journal. 2013;105(6):1357–1365. https://doi.org/10.1016/j.bpj.2013.07.050

18. Brunner J, Ragupathy S, Borchard G. Target specific tight junction modulators. Advanced Drug Delivery Reviews. 2021;171:266–288. https://doi.org/10.1016/j.addr.2021.02.008

19. Yang NJ, Hinner MJ. Getting across the cell membrane: An overview for small molecules, peptides, and proteins. Methods in Molecular Biology. 2015;1266:29–53. https://doi.org/10.1007/978-1-4939-2272-7_3

20. Kristensen M, Nielsen HM. Cell-penetrating peptides as carriers for oral delivery of biopharmaceuticals. Basic & Clinical Pharmacology & Toxicol. 2016;118(2):99–106. https://doi.org/10.1111/bcpt.12515

21. Salamat-Miller N, Johnston TP. Current strategies used to enhance the paracellular transport of therapeutic polypeptides across the intestinal epithelium. International Journal of Pharmaceutics. 2005;294(1–2):1–19. https://doi.org/10.1016/j.ijpharm.2005.01.022

22. Lee B, Moon KM, Kim CY. Tight junction in the intestinal epithelium: its association with diseases and regulation by phytochemicals. Journal of Immunology Research. 2018;2018:2645465. https://doi.org/10.1155/2018/2645465

23. Antosova Z, Mackova M, Kral V, Macek T. Therapeutic application of peptides and proteins: Parenteral forever? Trends in Biotechnology. 2009;27(11):628–635. https://doi.org/10.1016/j.tibtech.2009.07.009

24. Ensign LM, Cone R, Hanes J. Oral drug delivery with polymeric nanoparticles: The gastrointestinal mucus barriers. Advanced Drug Delivery Reviews. 2012;64(6):557–570. https://doi.org/10.1016/j.addr.2011.12.009

25. Canales C, Shleider C, Roque-Borda A, Cazorla JIM, Cazorla RMM, et al. Forging a new frontier: Antimicrobial peptides and nanotechnology converging to conquer gastrointestinal pathogens. Small. 2025;21(26):e2501431. https://doi.org/10.1002/smll.202501431

26. Zarrintaj P, Ghorbani S, Barani M, Chauhan NPS, Yazdi MK, et al. Polylysine for skin regeneration: A review of recent advances and future perspectives. Bioengineering & Translational Medicine. 2021;7(1):e10261. https://doi.org/10.1002/btm2.10261

27. Yaghmur A, Mu H. Recent advances in drug delivery applications of cubosomes, hexosomes, and solid lipid nanoparticles. Acta Pharmaceutica Sinica B. 2021;11(4):871–885. https://doi.org/10.1016/j.apsb.2021.02.013

28. Jansook P, Fülöp Z, Ritthidej GC. Amphotericin B loaded solid lipid nanoparticles (SLNs) and nanostructured lipid carrier (NLCs): Physicochemical and solid-solution state characterizations. Drug Development and Industrial Pharmacy. 2019;45(4):560–569. https://doi.org/10.1080/03639045.2019.1569023

29. Su L, Zhou F, Yu M, Ge R, He J, et al. Solid lipid nanoparticles enhance the resistance of oat-derived peptides that inhibit dipeptidyl peptidase IV in simulated gastrointestinal fluids. Journal of Functional Foods. 2020;65:103773. https://doi.org/10.1016/j.jff.2019.103773

30. Salvi VR, Pawar P. Nanostructured lipid carriers (NLC) system: A novel drug targeting carrier. Journal of Drug Delivery Science and Technology. 2019;51:255–267. https://doi.org/10.1016/j.jddst.2019.02.017

31. Elmowafy M, Al-Sanea MM. Nanostructured lipid carriers (NLCs) as drug delivery platform: Advances in formulation and application. Saudi Pharmaceutical Journal. 2021;29(9):999–1013. https://doi.org/10.1016/j.jsps.2021.07.015

32. Jain P, Rahi P, Pandey V, Asati S, Soni V. Nanostructured lipid carriers: A modish contrivance to overcome the ultraviolet effects. Egyptian Journal of Basic and Applied Sciences. 2017;4(2):89–100. https://doi.org/10.1016/j.ejbas.2017.02.001

33. Nelson AL, Mancino C, Gao X, Choe JA, Chubb L, et al. β-catenin mRNA encapsulated in SM-102 lipid nanoparticles enhances bone formation in a murine tibia fracture repair model. Bioactive Materials. 2024;39:273–286. https://doi.org/10.1016/j.bioactmat.2024.05.020

34. Akbari A, Saeedi M, Ahmadi F, Hashemi SMH, Babaei A, et al. Solid lipid nanoparticles and nanostructured lipid carriers: a review of the methods of manufacture and routes of administration. Pharmaceutical Development and Technology. 2022;27(5):525–539. https://doi.org/10.1080/10837450.2022.2084554

35. Chauhan I, Yasir M, Verma M, Singh AP. Nanostructured lipid carriers: A platform to lipophilic drug for oral bioavailability enhancement. Advanced Pharmaceutical Bulletin. 2020;10(2):150–165. https://doi.org/10.34172/apb.2020.021

36. Ehlers APF, Bartholomä J, Menghin D. Rechtliche Regelung der „Triage“ – Gesundheitssysteme an ihren Grenzen. Medizinrecht. 2021;39(5):416–423. [Ehlers APF, Bartholomä J, Menghin D. Legal regulation of "triage" health care systems at their borders. Medical Law. 2021;39(5):416–423. (In German)] https://doi.org/10.1007/s00350-021-5874-2

37. Fernández-Barat L, Ciofu O, Kragh KN, Pressler T, Johansen U, et al. Phenotypic shift in Pseudomonas aeruginosa populations from cystic fibrosis lungs after 2-week antipseudomonal treatment. Journal of Cystic Fibrosis. 2017;16:222–229. https://doi.org/10.1016/j.jcf.2016.08.005

38. Rehman KU, Zaman U, Alem A, Khan D, Khattak NS, et al. Alkaline protease functionalized hydrothermal synthesis of novel gold nanoparticles (ALPs-AuNPs): A new entry in photocatalytic and biological applications. International Journal of Biological Macromolecules. 2024;265:131067. https://doi.org/10.1016/j.ijbiomac.2024.131067

39. Silva APB, Roque-Borda CA, Carnero Canales CS, Duran Gleriani Primo LM, Silva IC, et al. Activity of bacteriophage D29 loaded on nanoliposomes against macrophages infected with Mycobacterium tuberculosis. Diseases. 2023;11(4):150. https://doi.org/10.3390/diseases11040150

40. Almeida A, Souto E. Solid lipid nanoparticles as a drug delivery system for peptides and proteins. Advanced Drug Delivery Reviews. 2007;59(6):478–490. https://doi.org/10.1016/j.addr.2007.04.007

41. Thapa RK, Diep DB, Tønnesen HH. Nanomedicine-based antimicrobial peptide delivery for bacterial infections: Recent advances and future prospects.Journal of Pharmaceutical Investigation. 2021;51(4):377–398. https://doi.org/10.1007/s40005-021-00525-z

42. Makowski M, Silva ÍC, Pais do Amaral C, Gonçalves S, Santos NC. Advances in lipid and metal nanoparticles for antimicrobial peptide delivery. Pharmaceutics. 2019;11(11):588. https://doi.org/10.3390/pharmaceutics11110588

43. Cantor S, Vargas L, Rojas A, Yarce C, Salamanca C, et al. Evaluation of antimicrobial peptide incorporated liposomes coated with Eudragit E-100 against foodborne pathogens. International Journal of Molecular Sciences. 2019;20(3):680. https://doi.org/10.3390/ijms20030680

44. Alzahrani NM, Booq RY, Aldossary AM, Bakr AA, Almughem FA, et al. Liposome-encapsulated tobramycin and IDR-1018 peptide mediated biofilm disruption and enhanced antimicrobial activity against Pseudomonas aeruginosa. Pharmaceutics. 2022;14(5):960. https://doi.org/10.3390/pharmaceutics14050960

45. Zhao H, Sun J, Cheng Y, Nie S, Li W. Advances in peptide/polymer antimicrobial assemblies. Journal of Materials Chemistry B. 2025;13(5):1518–1530. https://doi.org/10.1039/D4TB02144D

46. Spirescu VA, Chircov C, Grumezescu AM, Andronescu E. Polymeric nanoparticles for antimicrobial therapies: An up-to-date overview. Polymers (Basel). 2021;13(5):724. https://doi.org/10.3390/polym13050724

47. Fredenberg S, Wahlgren M, Reslow M, Axelsson A. The mechanisms of drug release in poly(lactic-co-glycolic acid)-based drug delivery systems – a review. International Journal of Pharmaceutics. 2011;415(1–2):34–52. https://doi.org/10.1016/j.ijpharm.2011.05.049

48. Sur S, Rathore A, Dave V, Reddy KR, Chouhan RS, et al. Recent developments in functionalized polymer nanoparticles for drug delivery. Nano-Structures & Nano-Objects. 2019;20:100397. https://doi.org/10.1016/j.nanoso.2019.100397

49. Giordani B, Basnet P, Mishchenko E, Luppi B, Škalko-Basnet N. Utilizing liposomal quercetin and gallic acid in localized treatment of vaginal Candida infections. Pharmaceutics. 2020;12:9. https://doi.org/10.3390/pharmaceutics12010009

50. Muthukrishnan L. Nanonutraceuticals – challenges and novel nano-based carriers for effective delivery and enhanced bioavailability. Food and Bioprocess Technology. 2022;15:2155–2184. https://doi.org/10.1007/s11947-022-02807-2

51. Zhuo S, Zhang F, Yu J, Zhang X, Yang G, et al. pH-sensitive biomaterials for drug delivery. Molecules. 2020;25(23):5649. https://doi.org/10.3390/molecules25235649

52. Roque-Borda CA, Saraiva MSM, Macedo Junior WD, Márquez Montesinos JCE, Meneguin AB, et al. Chitosan and HPMCAS double-coating as protective systems for alginate microparticles loaded with Ctx(Ile21)-Ha antimicrobial peptide to prevent intestinal infections. Biomaterials. 2023;293:121978. https://doi.org/10.1016/j.biomaterials.2022.121978

53. Tikhonov SL, Chernukha IM. Functional orientation of natural and synthesized biopeptides. Yekaterinburg: Ural State Forestry Engineering University and Ural State Agrarian University; 2024. 212 p. (In Russ.)

54. Raucher D, Ryu JS. Cell-penetrating peptides: Strategies for anticancer treatment. Trends in Molecular Medicine. 2015;21(9):560–570. https://doi.org/10.1016/j.molmed.2015.06.005

55. Douat C, Aisenbrey C, Antunes S, Decossas M, Lambert O, et al. A cell-penetrating foldamer with a bioreducible linkage for intracellular delivery of DNA. Angewandte Chemie International Edition. 2015;54(38):11133–11137. https://doi.org/10.1002/anie.201504884

56. Xie J, Bi Y, Zhang H, Dong S, Teng L, et al. Cell-penetrating peptides in diagnosis and treatment of human diseases: From preclinical research to clinical application. Frontiers in Pharmacology. 2020;11:697. https://doi.org/10.3389/fphar.2020.00697

57. Copolovici DM, Langel K, Eriste E, Langel U. Cell-penetrating peptides: Design, synthesis, and applications. ACS Nano. 2014;8(3):1972–1994. https://doi.org/10.1021/nn4057269

58. Wang T, Li H, Liang C, Sun S, Liu A, et al. Purification and characterization of a novel antioxidant Phelligridin LA produced by Inonotus baumii. Journal of Chemical Technology and Biotechnology. 2020;95(9):2483–2494. https://doi.org/10.1002/jctb.6430

59. Valieva SS, Tikhonov SL, Tikhonova NV, Timofeeva MS, Nogina AA. Synthesis and expression of a new recombinant food protein resistant to proteolysis and preventing aging processes. Agro-Industrial Complex of Russia. 2024;31(4):607–613. (In Russ.) https://doi.org/10.55934/2587-8824-2024-31-4-607-613

60. Zenin V, Tsedilin A, Yurkova M, Siniavin A, Fedorov A. Thermostable chaperone-based polypeptide biopolymer. PLOS One. 2023;18(6):e0286752. https://doi.org/10.1371/journal.pone.0286752

61. Deng C, Wu J, Cheng R, Meng F, Klok H-A, et al. Functional polypeptide and hybrid materials: Precision synthesis via α-amino acid N-carboxyanhydride polymerization and emerging biomedical applications. Progress in Polymer Science. 2014;39(2):330–364. https://doi.org/10.1016/j.progpolymsci.2013.10.008

62. Collins JM, Singh SK, White TA, Cesta DJ, Simpson CL, et al. Total wash elimination for solid phase peptide synthesis. Nature Communications. 2023;14(1):8168. https://doi.org/10.1038/s41467-023-44074-5

63. Liu Y, Li D, Ding J, Chen X. Controlled synthesis of polypeptides. Chinese Chemical Letters. 2020;31(12):3001–3014. https://doi.org/10.1016/j.cclet.2020.04.029

64. Varnava KG, Sarojini V. Making solid-phase peptide synthesis greener: A review of the literature. Chemistry an Asian Journal. 2019;14(8):1088–1097. https://doi.org/10.1002/asia.201801807

65. Lee YS. Gram-scale preparation of C-terminal-modified enkephalin analogues by typical liquid-phase peptide synthesis. Current Protocols in Protein Science. 2019;98(1):e97. https://doi.org/10.1002/cpps.97

66. Xu J, Wang F, Ye L, Wang R, Zhao L, et al. Penetrating peptides: Applications in drug delivery. Journal of Drug Delivery Science and Technology. 2023;84:104475. https://doi.org/10.1016/j.jddst.2023.104475

67. Kang Z, Ding G, Meng Z, Meng Q. The rational design of cell-penetrating peptides for application in delivery systems. Peptides. 2019;121:170149. https://doi.org/10.1016/j.peptides.2019.170149

68. Ruseska I, Zimmer A. Internalization mechanisms of cell-penetrating peptides. Beilstein Journal of Nanotechnology. 2020;11:101–123. https://doi.org/10.3762/bjnano.11.10

69. Cheng X, Chen K, Dong B, Yang M, Filbrun SL, et al. Dynamin-dependent vesicle twist at the final stage of clathrin-mediated endocytosis. Nature Cell Biology. 2021;23(8):859–869. https://doi.org/10.1038/s41556-021-00713-x

70. Liu Y, Shen Z, Xu Y, Zhu Y-W, Chen W, et al. Layer-by-layer self-assembly of PLL/CPP-ACP multilayer on SLA titanium surface: Enhancing osseointegration and antibacterial activity in vitro and in vivo. Colloids and Surfaces B: Biointerfaces. 2024;240:113966. https://doi.org/10.1016/j.colsurfb.2024.113966

71. Salloum G, Bresnick AR, Backer JM. Macropinocytosis: Mechanisms and regulation. Biochemical Journal. 2023;480(5):335–362. https://doi.org/10.1042/bcj20210584

72. Kim GC, Cheon DH, Lee Y. Challenge to overcome current limitations of cell-penetrating peptides. Biochimica et Biophysica Acta (BBA) – Proteins and Proteomics. 2021;1869(4):140604. https://doi.org/10.1016/j.bbapap.2021.140604

73. Kaplan IM, Wadia JS, Dowdy SF. Cationic TAT peptide transduction domain enters cells by macropinocytosis. Journal of Controlled Release. 2005;102(1):247–253. https://doi.org/10.1016/j.jconrel.2004.10.018

74. Eiriksdottir E, Mäger I, El Andaloussi S, Langel U, Lehto T. Cellular internalization kinetics of (luciferin-) cell-penetrating peptide conjugates. Bioconjugate Chemistry. 2010;21(9):1662–1672. https://doi.org/10.1021/bc100174y

75. Fittipaldi A, Ferrari A, Zoppé M, Arcangeli C, Pellegrini V, et al. Cell membrane lipid rafts mediate caveolar endocytosis of HIV-1 Tat fusion proteins. Journal of Biological Chemistry. 2003;278(36):34141–34149. https://doi.org/10.1074/jbc.M303045200

76. Mäger I, Langel K, Lehto T, Eiríksdóttir E, Langel Ü. The role of endocytosis on the uptake kinetics of luciferin-conjugated cell-penetrating peptides. Biochimica et Biophysica Acta (BBA) – Biomembranes. 2012;1818(3):502–511. https://doi.org/10.1016/j.bbamem.2011.11.020

77. Richard JP, Melikov K, Brooks H, Prevot P, Lebleu B, et al. Cellular uptake of unconjugated TAT peptide involves clathrin-dependent endocytosis and heparan sulfate receptors. Journal of Biological Chemistry. 2005;280(15):15300–15306. https://doi.org/10.1074/jbc.M401604200

78. Nakase I, Tadokoro A, Kawabata N, Takeuchi T, Katoh H, et al. Interaction of arginine-rich peptides with membrane-associated proteoglycans is crucial for induction of actin organization and macropinocytosis. Biochemistry. 2007;46(2):492–501. doihttps://doi.org/10.1021/bi0612824.

79. Subrizi A, Tuominen E, Bunker A, Róg T, Antopolsky M, et al. Tat(48-60) peptide amino acid sequence is not unique in its cell penetrating properties and cell-surface glycosaminoglycans inhibit its cellular uptake. Journal of Controlled Release. 2012;158(2):277–285. https://doi.org/10.1016/j.jconrel.2011.11.007

80. Wallbrecher R, Ackels T, Olea RA, Klein MJ, Caillon L, et al. Membrane permeation of arginine-rich cell-penetrating peptides independent of transmembrane potential as a function of lipid composition and membrane fluidity. Journal of Controlled Release. 2017;256:68–78. https://doi.org/10.1016/j.jconrel.2017.04.013

81. Szabő I, Mező G,Yousef MA, Soltész D, Bató C, et al. Redesigning of cell-penetrating peptides to improve their efficacy as a drug delivery system. Pharmaceutics. 2022;14(5):907. https://doi.org/10.3390/pharmaceutics14050907

82. Jiao C-Y, Delaroche D, Burlina F, Alves ID, Chassaing G, et al. Translocation and endocytosis for cell-penetrating peptide internalization. Journal Biological Chemistry. 2009;284(49):33957–33965. https://doi.org/10.1074/jbc.M109.056309

83. Li L, Vorobyov I, Allen TW. The different interactions of lysine and arginine side chains with lipid membranes. The Journal of Physical Chemistry B. 2013;117(40):11906–11920. https://doi.org/10.1021/jp405418y

84. Pirhaghi M, Mamashli F, Moosavi-Movahedi F, Arghavani P, Amiri A, et al. Cell-penetrating peptides: Promising therapeutics and drug-delivery systems for neurodegenerative diseases. Molecular Pharmaceutics. 2024;21(5):2097–2117. https://doi.org/10.1021/acs.molpharmaceut.3c01167

85. Zakany F, Mándity IM, Varga Z, Panyi G, Nagy P, et al. Effect of the lipid landscape on the efficacy of cell-penetrating peptides. Cells. 2023;12(13):1700. https://doi.org/10.3390/cells12131700

86. Byrne J, Huang H-W, McRae JC, Babaee S, Soltani A, et al. Devices for drug delivery in the gastrointestinal tract: A review of systems physically interacting with the mucosa for enhanced delivery. Advanced Drug Delivery Reviews. 2021;177:113940. https://doi.org/10.1016/j.addr.2021.113926

87. Homayun B, Lin X, Choi H-J. Challenges and recent progress in oral drug delivery systems for biopharmaceuticals. Pharmaceutics. 2019;11(3):129. https://doi.org/10.3390/pharmaceutics11030129

88. Vazquez-Uribe R, Hedin KA, Licht TR, Nieuwdorp M, Sommer MOA. Advanced microbiome therapeutics as a novel modality for oral delivery of peptides to manage metabolic diseases. Trends in Endocrinology and Metabolism. 2024;35(9):779–791. https://doi.org/10.1016/j.tem.2024.04.021

89. Hedin KA, Rees VM, Zhang H, Kruse V, Vazquez-Uribe R, et al. Effects of broad-spectrum antibiotics on the colonisation of probiotic yeast Saccharomyces boulardii in the murine gastrointestinal tract. Scientific Reports. 2022;12(1):8862. https://doi.org/10.1038/s41598-022-12806-0

90. Vaaben TH, Vazquez-Uribe R, Sommer MOA. Characterization of eight bacterial biosensors for microbial diagnostic and therapeutic applications. ACS Synthetic Biology. 2022;11(12):4184–4193. https://doi.org/10.1021/acssynbio.2c00491

91. Redden H, Morse N, Alper HS. The synthetic biology toolbox for tuning gene expression in yeast. FEMS Yeast Res. 2015;15(1):1–10. https://doi.org/10.1111/1567-1364.12188

92. Sands C, Hedin KA, Vazquez-Uribe R, Sommer MOA. Saccharomyces boulardii promoters for control of gene expression in vivo. Microbial Cell Factories. 2024;23(1):16. https://doi.org/10.1186/s12934-023-02288-8

93. Armetta J, Schantz-Klausen M, Shepelin D, Vazquez-Uribe R, Bahl MI. Escherichia coli promoters with consistent expression throughout the murine gut. ACS Synthetic Biology. 2021;10(12):3359–3367. https://doi.org/10.1021/acssynbio.1c00325

94. Durmusoglu D, Naldi M, Parolin C, Erdoğan Ü, Bartolini M, et al. Improving therapeutic protein secretion in the probiotic yeast Saccharomyces boulardii using a multifactorial engineering approach. Microbial Cell Factories. 2023;22(1):45. https://doi.org/10.1186/s12934-023-02053-x

95. Santos-Navarro FN, Vignoni A, Boada Y, Pico J. RBS and promoter strengths determine the cell-growth-dependent protein mass fractions and their optimal synthesis rates. ACS Synthetic Biology. 2021;10(12):3297–3308. https://doi.org/10.1021/acssynbio.1c00131

96. Oesterle S, Gerngross D, Schmitt S, Roberts TM, Panke S. Efficient engineering of chromosomal ribosome binding site libraries in mismatch repair proficient Escherichia coli. Scientific Reports. 2017;7(1):123. https://doi.org/10.1038/s41598-017-12395-3

97. Felippes de FF, Mchale M, Doran RL, Roden S, Eamens AL, et al. The key role of terminators on the expression and posttranscriptional gene silencing of transgenes. The Plant Journal. 2020;104(1):96–112. https://doi.org/10.1111/tpj.14907

98. Bose A, Wong TW, Singh N. Formulation development and optimization of sustained release matrix tablet of Itopride HCl by response surface methodology and its evaluation of release kinetics. Saudi Pharmaceutical Journal. 2013;21(2):201–213. https://doi.org/10.1016/j.jsps.2012.03.006

99. Reddy N, Reddy R, Jiang Q. Crosslinking biopolymers for biomedical applications. Trends in Biotechnology. 2015;33(6):362–369. https://doi.org/10.1016/j.tibtech.2015.03.008

100. Jiang G, Woo BH, Kang F, Singh J, Deluca PP. Assessment of protein release kinetics, stability and protein polymer interaction of lysozyme encapsulated poly(D,L-lactide-co-glycolide) microspheres. Journal of Controlled Release. 2002;79(1-3):137–145. https://doi.org/10.1016/S0168-3659(01)00533-8

101. Charbonneau MR, Isabella VM, Li N, Kurtz CB. Developing a new class of engineered live bacterial therapeutics to treat human diseases. Nature Communications. 2020;11(1):1738. https://doi.org/10.1038/s41467-020-15508-1

102. Brennan AM. Development of synthetic biotics as treatment for human diseases. Synthetic Biology. 2022;7(1):ysac014. https://doi.org/10.1093/synbio/ysac001

103. Ozdemir T, Fedorec AJH, Barnes CP, Danino T, et al. Synthetic biology and engineered live biotherapeutics: Toward increasing system complexity. Cell Systems. 2018;7(1):5–16. https://doi.org/10.1016/j.cels.2018.06.008

104. Heavey MK, Durmusoglu D, Crook N, Anselmo AC. Discovery and delivery strategies for engineered live biotherapeutic products. Trends Biotechnol. 2022;40(3):354–369. https://doi.org/10.1016/j.tibtech.2021.08.002

105. Rutter JW, Dekker L, Owen KA, Barnes CP. Microbiome engineering: Engineered live biotherapeutic products for treating human disease. Frontiers in Bioengineering and Biotechnology. 2022;10:892087. https://doi.org/10.3389/fbioe.2022.1000873

106. Chien T, Harimoto T, Kepecs B, Gray K, Coker C, et al. Enhancing the tropism of bacteria via genetically programmed biosensors. Nature Biomedical Engineering. 2022;6(9):1052–1063. https://doi.org/10.1038/s41551-021-00772-3

107. Armstrong A, Isalan M. Engineering bacterial theranostics: From logic gates to in vivo applications. Frontiers in Bioengineering and Biotechnology. 2022;10:892087. https://doi.org/10.3389/fbioe.2024.1437301

108. Hedin KA, Kruse V, Vazquez-Uribe R, Sommer MOA. Biocontainment strategies for in vivo applications of Saccharomyces boulardii. Frontiers in Bioengineering and Biotechnology. 2023;11:1136095. https://doi.org/10.3389/fbioe.2023.1136095

109. Ma Y, Manna A, Moon TS. Advances in engineering genetic circuits for microbial biocontainment. Current Opinion in Systems Biology. 2021;36:100483. https://doi.org/10.1016/j.coisb.2023.100483

110. Arnold JA, Glazier J, Mimee M. Genetic engineering of resident bacteria in the gut microbiome. Journal of Bacteriol. 2023;205(7):e0012723. https://doi.org/10.1128/jb.00127-23

111. Hayashi N, Lai Y, Fuerte-Stone J, Mimee M, Lu TK. Cas9-assisted biological containment of a genetically engineered human commensal bacterium and genetic elements. Nature Communications. 2024;15(1):2096. https://doi.org/10.1038/s41467-024-45893-w

112. Xing H, Liu X, Wang JU, Zhou T, Jin X, et al. Magnetically targeted delivery of probiotics for controlled residence and accumulation in the intestine. Nanoscale. 2025;17(15):8588–8598. https://doi.org/10.1039/d4nr04753b

113. Charbonneau MR, Denney WS, Horvath NG, Cantarella P, Castillo MJ, et al. Development of a mechanistic model to predict synthetic biotic activity in healthy volunteers and patients with phenylketonuria. Communications Biology. 2021;4(1):89. https://doi.org/10.1038/s42003-021-02183-1

114. Cone RA. Barrier properties of mucus. Advanced Drug Delivery Reviews. 2009;61(2):75–85. https://doi.org/10.1016/j.addr.2008.09.008

115. Chen M-C, Sonaje K, Chen K-J, Sung H-W. A review of the prospects for polymeric nanoparticle platforms in oral insulin delivery. Biomaterials. 2011;32(36):9826–9838. https://doi.org/10.1016/j.biomaterials.2011.08.087

116. Zizzari AT, Pliatsika D, Gall FM, Fischer T, Riedl R. New perspectives in oral peptidomimetic delivery. Drug Discovery Today. 2021;26(4):1097–1105. https://doi.org/10.1016/j.drudis.2021.01.020


Login or Create
* Forgot password?