The Journal of Membrane Biology

, Volume 252, Issue 6, pp 527–539 | Cite as

Direct Drug Targeting into Intracellular Compartments: Issues, Limitations, and Future Outlook

  • Gamaleldin I. HarisaEmail author
  • Tarek M. Faris
Topical Review


Intracellular compartment drug delivery is a promising strategy for the treatment of diseases. By this way, medicines can delivered to particular intracellular compartments. This maximizes the therapeutic efficacy and safety of medicines, particularly of anticancer and antiviral drugs. Intracellular compartment drug delivery is either indirectly by targeting of cell nucleus as central compartment of the cell or directly through the targeting of compartments itself. Drugs or nanoshuttles labeled with compartment’s localization signal represent a smart tactic for subcellular compartment targeting. There are several boundaries prevent the arrival of shuttles to the specified intracellular compartments. These boundaries include selective permeability of biomembranes, efflux transporters, and lysosomes. The utilization of specific ligands during design of drug delivery nanoshuttles permits the targeting of specified intracellular compartment. Therefore drugs targeting could correct the diseases associated organelles. This review highlights the direct targeting of the medicines into subcellular compartment as a promising therapeutic strategy.


Biological zip code Nanoshuttles Mitochondria Proteosome Peroxisome 



The authors extend their appreciation to the Vice Research Chairs at King Saud University, Saudi Arabia for funding this work through Kayyali Chair for Pharmaceutical Industry, Department of Pharmaceutics, College of Pharmacy, King Saud University, for funding the work through Grant Number G-2019-1.

Compliance with Ethical Standards

Conflict of interest

The authors declare that there are no conflicts of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. Adjei IM, Sharma B, Labhasetwar V (2014) Nanoparticles: cellular uptake and cytotoxicity. Adv Exp Med Biol 811:73–91PubMedGoogle Scholar
  2. Aresh W, Liu Y, Sine J, Thayer D, Puri A, Huang Y, Nieh MP (2016) The morphology of self-assembled lipid-based nanoparticles affects their uptake by cancer cells. J Biomed Nanotechnol 12(10):1852–1863. CrossRefPubMedGoogle Scholar
  3. Barua S, Yoo J-W, Kolhar P, Wakankar A, Gokarn YR, Mitragotri S (2013) Particle shape enhances specificity of antibody-displaying nanoparticles. Proc Natl Acad Sci 110:3270–3275PubMedGoogle Scholar
  4. Biswas S, Torchilin VP (2014) Nanopreparations for organelle-specific delivery in cancer. Adv Drug Deliv Rev 66:26–41PubMedGoogle Scholar
  5. Buzea C, Pacheco II, Robbie K (2007) Nanomaterials and nanoparticles: sources and toxicity. Biointerphases 2:MR17–MR71PubMedGoogle Scholar
  6. Byrne JD, Betancourt T, Brannon-Peppas L (2008) Active targeting schemes for nanoparticle systems in cancer therapeutics. Adv Drug Deliv Rev 60:1615–1626PubMedGoogle Scholar
  7. Cao B, Mao X (2011) The ubiquitin-proteasomal system is critical for multiple myeloma: implications in drug discovery. Am J Blood Res 1:46–56PubMedPubMedCentralGoogle Scholar
  8. Chandrawati R, Caruso F (2012) Biomimetic liposome- and polymersome-based multicompartmentalized assemblies. Langmuir 28:13798–13807PubMedGoogle Scholar
  9. Chithrani BD, Chan WCW (2007) Elucidating the mechanism of cellular uptake and removal of protein-coated gold nanoparticles of different sizes and shapes. Nano Lett 7:1542–1550PubMedGoogle Scholar
  10. Doherty GJ, McMahon HT (2009) Mechanisms of endocytosis. Annu Rev Biochem 78:857–902PubMedGoogle Scholar
  11. Fang RH, Jiang Y, Fang JC, Zhang L (2017) Cell membrane-derived nanomaterials for biomedical applications. Biomaterials 128:69–83PubMedPubMedCentralGoogle Scholar
  12. Fröhlich E (2012) The role of surface charge in cellular uptake and cytotoxicity of medical nanoparticles. Int J Nanomed 7:5577–5591Google Scholar
  13. Gadhave K, Bolshette N, Ahire A, Pardeshi R, Thakur K, Trandafir C et al (2016) The ubiquitin proteasomal system: a potential target for the management of Alzheimer’s disease. J Cell Mol Med 20:1392–1407PubMedPubMedCentralGoogle Scholar
  14. Gu ZC, Enenkel C (2014) Proteasome assembly. Cell Mol Life Sci 71:4729–4745PubMedGoogle Scholar
  15. Ha D, Yang N, Nadithe V (2016) Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges. Acta Pharm Sin B 6:287–296PubMedPubMedCentralGoogle Scholar
  16. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674Google Scholar
  17. Harisa GI, Badran MM, Alanazi FK, Attia SM (2017) Crosstalk of nanosystems induced extracellular vesicles as promising tools in biomedical applications. J Membr Biol 250:605–616PubMedGoogle Scholar
  18. Harisa GI, Badran MM, Alanazi FK, Attia SM (2018) An overview of nanosomes delivery mechanisms: trafficking, orders, barriers and cellular effects. Artif Cells Nanomed Biotechnol 46:669–679PubMedGoogle Scholar
  19. Hatakeyama H, Ito E, Akita H, Oishi M, Nagasaki Y, Futaki S et al (2009) A pH-sensitive fusogenic peptide facilitates endosomal escape and greatly enhances the gene silencing of siRNA-containing nanoparticles in vitro and in vivo. J Control Release 139:127–132PubMedGoogle Scholar
  20. Healy SJM, Gorman AM, Mousavi-Shafaei P, Gupta S, Samali A (2009) Targeting the endoplasmic reticulum-stress response as an anticancer strategy. Eur J Pharmacol 625:234–246PubMedGoogle Scholar
  21. Heller A, Brockhoff G, Goepferich A (2012) Targeting drugs to mitochondria. Eur J Pharm Biopharm 82:1–18PubMedGoogle Scholar
  22. Hild WA, Breunig M, Goepferich A (2008) Quantum dots—nano-sized probes for the exploration of cellular and intracellular targeting. Eur J Pharm Biopharm 68:153–168PubMedGoogle Scholar
  23. Horton KL, Stewart KM, Fonseca SB, Guo Q, Kelley SO (2008) Mitochondria-penetrating peptides. Chem Biol 15:375–382PubMedGoogle Scholar
  24. Indran IR, Tufo G, Pervaiz S, Brenner C (2011) Recent advances in apoptosis, mitochondria and drug resistance in cancer cells. Biochim Biophys Acta 1807:735–745PubMedGoogle Scholar
  25. Ivanov AI (2014) Pharmacological inhibitors of exocytosis and endocytosis: novel bullets for old targets. In: Ivanov AI (ed) Exocytosis and endocytosis. Springer, New York, pp 3–18Google Scholar
  26. Jhaveri A, Torchilin V (2016) Intracellular delivery of nanocarriers and targeting to subcellular organelles. Expert Opin Drug Deliv 13:49–70PubMedGoogle Scholar
  27. Johnsen KB, Gudbergsson JM, Skov MN, Pilgaard L, Moos T, Duroux M (2014) A comprehensive overview of exosomes as drug delivery vehicles—endogenous nanocarriers for targeted cancer therapy. Biochim Biophys Acta 1846:75–87Google Scholar
  28. Kettler K, Veltman K, van de Meent D, van Wezel A, Hendriks AJ (2014) Cellular uptake of nanoparticles as determined by particle properties, experimental conditions, and cell type. Environ Toxicol Chem 33:481–492PubMedGoogle Scholar
  29. Kolhar P, Anselmo AC, Gupta V, Pant K, Prabhakarpandian B, Ruoslahti E et al (2013) Using shape effects to target antibody-coated nanoparticles to lung and brain endothelium. Proc Natl Acad Sci 110:10753–10758PubMedGoogle Scholar
  30. Kotmakçı M, Çetintaş VB (2015) Extracellular vesicles as natural nanosized delivery systems for small-molecule drugs and genetic material: steps towards the future nanomedicines. J Pharm Pharm Sci 18:396–413PubMedGoogle Scholar
  31. Kou L, Sun J, Zhai Y, He Z (2013) The endocytosis and intracellular fate of nanomedicines: implication for rational design. Asian J Pharm Sci 8:1–10Google Scholar
  32. Kumar D, Sharma D, Singh G, Singh M, Rathore MS (2012) Lipoidal soft hybrid biocarriers of supramolecular construction for drug delivery. ISRN Pharm 14:474830Google Scholar
  33. Kumar A, Chen F, Mozhi A, Zhang X, Zhao Y, Xue X et al (2013) Innovative pharmaceutical development based on unique properties of nanoscale delivery formulation. Nanoscale 5:8307–8325PubMedPubMedCentralGoogle Scholar
  34. Kwon EJ, Bergen JM, Pun SH (2008) Application of an HIV gp41-derived peptide for enhanced intracellular trafficking of synthetic gene and siRNA delivery vehicles. Bioconjug Chem 19:920–927PubMedGoogle Scholar
  35. Li Z, Zhang Y, Zhu D, Li S, Yu X, Zhao Y et al (2017) Transporting carriers for intracellular targeting delivery via non-endocytic uptake pathways. Drug Deliv 24:45–55PubMedGoogle Scholar
  36. Lin R, Zhang P, Cheetham AG, Walston J, Abadir P, Cui H (2015) Dual peptide conjugation strategy for improved cellular uptake and mitochondria targeting. Bioconjug Chem 26:71–77PubMedGoogle Scholar
  37. Lip PZY, Demasi M, Bonatto D (2017) The role of the ubiquitin proteasome system in the memory process. Neurochem Int 102:57–65PubMedGoogle Scholar
  38. Lub S, Maes K, Menu E, De Bruyne E, Vanderkerken K, Van Valckenborgh E (2016) Novel strategies to target the ubiquitin proteasome system in multiple myeloma. Oncotarget 7:6521–6537PubMedGoogle Scholar
  39. Luk BT, Zhang L (2015) Cell membrane-camouflaged nanoparticles for drug delivery. J Control Release 220:600–607PubMedPubMedCentralGoogle Scholar
  40. Maity AR, Stepensky D (2015) Delivery of drugs to intracellular organelles using drug delivery systems: analysis of research trends and targeting efficiencies. Int J Pharm 496:268–274PubMedGoogle Scholar
  41. Malhi SS, Murthy RSR (2012) Delivery to mitochondria: a narrower approach for broader therapeutics. Expert Opin Drug Deliv 9:909–935PubMedGoogle Scholar
  42. Matlin KS (2011) Spatial expression of the genome: the signal hypothesis at forty. Nat Rev Mol Cell Biol 12:333–340PubMedGoogle Scholar
  43. Nagayama S, Ogawara K-i, Fukuoka Y, Higaki K, Kimura T (2007) Time-dependent changes in opsonin amount associated on nanoparticles alter their hepatic uptake characteristics. Int J Pharm 342:215–221PubMedGoogle Scholar
  44. Noble GT, Stefanick JF, Ashley JD, Kiziltepe T, Bilgicer B (2014) Ligand-targeted liposome design: challenges and fundamental considerations. Trends Biotechnol 32:32–45PubMedGoogle Scholar
  45. Oh N, Park J-H (2014) Endocytosis and exocytosis of nanoparticles in mammalian cells. Int J Nanomed 9:51–63Google Scholar
  46. Oppici E, Fargue S, Reid ES, Mills PB, Clayton PT, Danpure CJ et al (2015) Pyridoxamine and pyridoxal are more effective than pyridoxine in rescuing folding-defective variants of human alanine:glyoxylate aminotransferase causing primary hyperoxaluria type I. Hum Mol Genet 24:5500–5511PubMedGoogle Scholar
  47. Panariti A, Miserocchi G, Rivolta I (2012) The effect of nanoparticle uptake on cellular behavior: disrupting or enabling functions? Nanotechnol Sci Appl 5:87–100PubMedPubMedCentralGoogle Scholar
  48. Prokop A, Davidson JM (2008) Nanovehicular intracellular delivery systems. J Pharm Sci. 97(9):3518–3590PubMedPubMedCentralGoogle Scholar
  49. Roncador A, Oppici E, Talelli M, Pariente AN, Donini M, Dusi S et al (2017) Use of polymer conjugates for the intraperoxisomal delivery of engineered human alanine: glyoxylate aminotransferase as a protein therapy for primary hyperoxaluria type I. Nanomedicine: nanotechnology. Biol Med 13:897–907Google Scholar
  50. Sahoo SK, Ma W, Labhasetwar V (2004) Efficacy of transferrin-conjugated paclitaxel-loaded nanoparticles in a murine model of prostate cancer. Int J Cancer 112:335–340PubMedGoogle Scholar
  51. Sakhrani NM, Padh H (2013) Organelle targeting: third level of drug targeting. Drug Des Dev Therapy 7:585–599Google Scholar
  52. Sakhtianchi R, Minchin RF, Lee KB, Alkilany AM et al (2013) Exocytosis of nanoparticles from cells: role in cellular retention and toxicity. Adv Colloid Interface Sci 201–202:18–29PubMedGoogle Scholar
  53. Salvati A, Pitek AS, Monopoli MP, Prapainop K, Bombelli FB, Hristov DR et al (2013) Transferrin-functionalized nanoparticles lose their targeting capabilities when a biomolecule corona adsorbs on the surface. Nat Nanotechnol 8:137–143PubMedGoogle Scholar
  54. Sato YT, Umezaki K, Sawada S, Mukai S-A, Sasaki Y, Harada N et al (2016) Engineering hybrid exosomes by membrane fusion with liposomes. Sci Rep 6:21933PubMedPubMedCentralGoogle Scholar
  55. Schmitt C, Lippert AH, Bonakdar N, Sandoghdar V, Voll LM (2016) Compartmentalization and transport in synthetic vesicles. Front Bioeng Biotechnol 4:4–19Google Scholar
  56. Selbo PK, Weyergang A, Høgset A, Norum O-J, Berstad MB, Vikdal M et al (2010) Photochemical internalization provides time- and space-controlled endolysosomal escape of therapeutic molecules. J Control Release 148:2–12PubMedGoogle Scholar
  57. Shrestha R, Elsabahy M, Florez-Malaver S, Samarajeewa S, Wooley KL (2012) Endosomal escape and siRNA delivery with cationic shell crosslinked knedel-like nanoparticles with tunable buffering capacities. Biomaterials 33:8557–8568PubMedPubMedCentralGoogle Scholar
  58. Song Q, Li D, Zhou Y, Yang J, Yang W, Zhou G et al (2014) Enhanced uptake and transport of (+)-catechin and (-)-epigallocatechin gallate in niosomal formulation by human intestinal Caco-2 cells. Int J Nanomed 9:2157–2165Google Scholar
  59. Srivastava A, Babu A, Filant J, Moxley K, Ruskin R, Dhanasekaran D et al (2016) Exploitation of exosomes as nanocarriers for gene-, chemo-, and immune-therapy of cancer. J Biomed Nanotechnol 12:1159–1173Google Scholar
  60. Terlecky SR, Koepke JI (2007) Drug delivery to peroxisomes: employing unique trafficking mechanisms to target protein therapeutics. Adv Drug Deliv Rev 59:739–747PubMedGoogle Scholar
  61. Theodossiou TA, Sideratou Z, Katsarou ME, Tsiourvas D (2013) Mitochondrial delivery of doxorubicin by triphenylphosphonium-functionalized hyperbranched nanocarriers results in rapid and severe cytotoxicity. Pharm Res 30:2832–2842PubMedGoogle Scholar
  62. Treuel L, Jiang X, Nienhaus GU (2013) New views on cellular uptake and trafficking of manufactured nanoparticles. J R Soc Interface 10:20120939PubMedPubMedCentralGoogle Scholar
  63. Varkouhi AK, Scholte M, Storm G, Haisma HJ (2011) Endosomal escape pathways for delivery of biologicals. J Control Release 151:220–228PubMedGoogle Scholar
  64. Wang P, Wang X, Wang L, Hou X, Liu W, Chen C (2015) Interaction of gold nanoparticles with proteins and cells. Sci Technol Adv Mater 16:034610PubMedPubMedCentralGoogle Scholar
  65. Wlodkowic D, Skommer J, McGuinness D, Hillier C, Darzynkiewicz Z (2009) ER–Golgi network—a future target for anti-cancer therapy. Leuk Res 33:1440–1447PubMedPubMedCentralGoogle Scholar
  66. Yamada Y, Harashima H (2017) MITO-porter for mitochondrial delivery and mitochondrial functional analysis. In: Singh H, Sheu S-S (eds) Pharmacology of mitochondria. Springer, Cham, pp 457–472Google Scholar
  67. Yameen B, Choi WI, Vilos C, Swami A, Shi J, Farokhzad OC (2014) Insight into nanoparticle cellular uptake and intracellular targeting. J Control Release 190:485–499PubMedPubMedCentralGoogle Scholar
  68. Yang P-H, Sun X, Chiu J-F, Sun H, He Q-Y (2005) Transferrin-mediated gold nanoparticle cellular uptake. Bioconjug Chem 16:494–496PubMedGoogle Scholar
  69. Zhang Y, Tekobo S, Tu Y, Zhou Q, Jin X, Dergunov SA et al (2012) Permission to enter cell by shape: nanodisk vs nanosphere. ACS Appl Mater Interfaces 4:4099–4105PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Kayyali Chair for Pharmaceutical Industry, College of PharmacyKing Saud UniversityRiyadhSaudi Arabia
  2. 2.Department of Pharmaceutics, College of PharmacyKing Saud UniversityRiyadhSaudi Arabia
  3. 3.Department of Biochemistry, College of PharmacyAl-Azhar UniversityCairoEgypt
  4. 4.Department of Pharmaceutics, Faculty of PharmacyAl-Azhar UniversityCairoEgypt

Personalised recommendations