Biosensors and Nanotheranostics
Bionanotechnology, Drug Delivery, Therapeutics | online ISSN 3064-7789
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Volume 5 Number 1 2026
REVIEWS (Open Access)
Engineering Reproducible Theranostic Liposomes Through Continuous-Flow Microfluidics
Umayyah Osman 1*, Adam Shah Abdul Majid 1
Biosensors and Nanotheranostics 5 (1) 1-8 https://doi.org/10.25163/biosensors.5110986
Submitted: 29 April 2026 Revised: 14 June 2026 Accepted: 25 June 2026 Published: 27 June 2026
Abstract
Liposomes remain the most clinically validated class of nanocarriers, yet the step that most often decides whether a promising theranostic formulation ever reaches patients is not its design but its manufacture. Conventional bulk methods, such as thin-film hydration and ethanol injection, rely on chaotic macroscale mixing that yields polydisperse, frequently multilamellar vesicles and demands harsh post-processing, leaving a batch-to-batch variability that is difficult to reconcile with Good Manufacturing Practice (GMP). This review examines how microfluidic continuous-flow manufacturing has reframed that problem. Operating within sub-millimetre channels under laminar, diffusion-dominated flow, microfluidic platforms assemble size-tunable (approximately 20 to 200 nm), narrowly dispersed (PDI < 0.2) small unilamellar vesicles in a single step, with critical quality attributes governed predictably by the flow rate ratio and total flow rate. We synthesize evidence that this control translates into theranostic performance: two- to three-fold higher loading of hydrophobic photosensitizers and metallic nanoparticles, cleaner co-encapsulation of multi-modal cargoes such as doxorubicin with gadolinium chelates, gold nanorods, or iron oxide, and measurable gains in MRI relaxivity and triggered release. We then revisit the scale-up question long separating bench elegance from clinical supply, comparing parallelization, 3D-printed multilayer chips (up to 474 mL/min), and vortex focusing (exceeding 20 g/h) as routes to industrial throughput without surrendering monodispersity. Finally, we outline how Quality by Design and in-line Process Analytical Technology close the loop toward automated, regulation-ready production. Taken together, the literature suggests that microfluidics is maturing from a characterization tool into a credible manufacturing paradigm, even as standardization and regulatory precedent remain unfinished.
Keywords: theranostic liposomes; microfluidics; hydrodynamic flow focusing; process intensification; Quality by Design; Process Analytical Technology; co-encapsulation; GMP manufacturing.
References
Al-Ahmady, Z., Lozano, N., Mei, K. C., Al-Jamal, W. T., & Kostarelos, K. (2018). Engineering thermosensitive liposome-nanoparticle hybrids loaded with doxorubicin for heat-triggered drug release / Fabrication of hybrids of liposomes and hydrophobic gold nanoparticles using a microfluidic assisted self-assembly process. International Journal of Pharmaceutics, 514(1), 133-141. https://doi.org/10.1016/j.ijpharm.2016.03.048
Amrani, S., & Tabrizian, M. (2018). Characterization of nanoscale loaded liposomes produced by 2D hydrodynamic flow focusing. ACS Biomaterials Science & Engineering, 4(2), 502-513. https://doi.org/10.1021/acsbiomaterials.7b00788
Ballacchino, G., Weaver, E., Mathew, E., Dorati, R., Genta, I., Conti, B., & Lamprou, D. A. (2021). Manufacturing of 3D-printed microfluidic devices for the synthesis of drug-loaded liposomal formulations. International Journal of Molecular Sciences, 22(15), 8064. https://doi.org/10.3390/ijms22158064
Basak, S., Das, T. K., & Co-authors. (2025). Evolution of liposomes from laboratory models to clinically approved therapeutics: Scale-up, batch consistency, and regulatory perspectives. ChemEngineering, 9(3), 56. https://doi.org/10.3390/chemengineering9030056
Bozzuto, G., & Molinari, A. (2015). Liposomes as nanomedical devices. International Journal of Nanomedicine, 10, 975-999. https://doi.org/10.2147/IJN.S68861
Dai, Y., Su, J., Wu, K., Ma, W., Wang, B., Li, M., Sun, P., Shen, Q., Wang, Q., & Fan, Q. (2019). Multifunctional thermosensitive liposomes based on natural phase-change material: Near-infrared light-triggered drug release and multimodal imaging-guided cancer combination therapy. ACS Applied Materials & Interfaces, 11(11), 10540-10553. https://doi.org/10.1021/acsami.8b22687
Fernandes, D. A., Appak-Baskoy, S., Berndl, E., & Kolios, M. C. (2023). Multifunctional nanoparticles and thermosensitive liposomes for theranostic applications and multimodal imaging-guided combination therapy. Pharmaceutics, 15(9), 2448. https://doi.org/10.3390/pharmaceutics15092448
Han, J. Y., La Fiandra, J. N., & DeVoe, D. L. (2022). Microfluidic vortex focusing for high throughput synthesis of size-tunable liposomes. Nature Communications, 13, 6997. https://doi.org/10.1038/s41467-022-34750-3
Jahn, A., Vreeland, W. N., Gaitan, M., & Locascio, L. E. (2004). Controlled vesicle self-assembly in microfluidic channels with hydrodynamic focusing. Journal of the American Chemical Society, 126(9), 2674-2675. https://doi.org/10.1021/ja0318031
Kabay, G., & Co-authors. (2022). Microfluidic manufacturing of lipid-based theranostic nanoparticles and in-line process validation. Small Methods, 6(5), 2101234. https://doi.org/10.1002/smtd.202101234
Kastner, E., Kaur, R., Lowry, D., Moghaddam, B., Wilkinson, A., & Perrie, Y. (2014). High-throughput manufacturing of size-tuned liposomes by a new microfluidics method using enhanced statistical tools for characterization. International Journal of Pharmaceutics, 477(1-2), 361-368. https://doi.org/10.1016/j.ijpharm.2014.10.030
Khadke, S., Roces, C. B., Cameron, A., Devitt, A., & Perrie, Y. (2019). Formulation and manufacturing of lymphatic targeting liposomes using microfluidics. Journal of Controlled Release, 307, 211-220. https://doi.org/10.1016/j.jconrel.2019.06.012
Kiuchi, M., Takeoka, S., & Sou, K. (2025). Microfluidic preparation of size- and lamellarity-controlled liposomes using a static mixer and the advantage of a multilamellar structure in biosensing applications. Frontiers in Bioengineering and Biotechnology, 13, 1715496. https://doi.org/10.3389/fbioe.2025.1715496
Lammers, T., Aime, S., Hennink, W. E., Storm, G., & Kiessling, F. (2011). Theranostic nanomedicine. Accounts of Chemical Research, 44(10), 1029-1038.
Lamprou, D. A., & Co-authors. (2021). Microfluidic manufacturing of lipid-based nanoparticles: Advantages over conventional methods. Nanomaterials, 11(12), 3440. https://doi.org/10.3390/nano11123440
Liu, D., & Co-authors. (2022). Microfluidic devices for scale-up or scale-out production of nanoparticles for drug delivery. Small, 18(10), 2105872. https://doi.org/10.1002/smll.202106580
Lu, Y., & Co-authors. (2016). Liposomes as nanocarriers for theranostic applications. Theranostics, 6(9), 1336-1352.
Lv, S., Jing, R., Liu, X., Shi, H., Shi, Y., Wang, X., Zhao, X., Cao, K., & Lv, Z. (2021). One-step microfluidic fabrication of multi-responsive liposomes for targeted delivery of doxorubicin synergism with photothermal effect. International Journal of Nanomedicine, 16, 7759-7772. https://doi.org/10.2147/IJN.S334321
Ota, A., Mochizuki, A., Sou, K., & Takeoka, S. (2023). Evaluation of a static mixer as a new microfluidic method for liposome formulation. Frontiers in Bioengineering and Biotechnology, 11, 1229829. https://doi.org/10.3389/fbioe.2023.1229829
Patel, R., Morker, K., & Purohit, D. (2025). Comprehensive analytical characterization and Quality by Design (QbD) approach in liposomal formulation development. International Journal of Pharmaceutical Sciences, 3(3), 2005-2021. https://doi.org/10.3390/ijms26033820
Pharmaceutics Review. (2025). Regulatory perspectives, Quality by Design, and theranostic liposome process validation under GMP guidelines. Pharmaceutics, 17(1), 1588.
Ran, R., Middelberg, A. P. J., & Zhao, C. X. (2016). Microfluidic synthesis of multifunctional liposomes for tumour targeting. Colloids and Surfaces B: Biointerfaces, 148, 402-410. https://doi.org/10.1016/j.colsurfb.2016.08.032
Shan, H., Lin, Q., Wang, D., Sun, X., Quan, B., Chen, X., & Chen, Z. (2021). 3D printed integrated multi-layer microfluidic chips for ultra-high volumetric throughput nanoliposome preparation. Frontiers in Bioengineering and Biotechnology, 9, 773705. https://doi.org/10.3389/fbioe.2021.773705
Skupin-Mrugalska, P., Sobotta, L., Warowicka, A., Wereszczynska, B., Zalewski, T., Gierlich, P., Jarek, M., Nowaczyk, G., Kempka, M., Gapinski, J., Jurga, S., & Mielcarek, J. (2018). Theranostic liposomes as a bimodal carrier for magnetic resonance imaging contrast agent and photosensitizer. Journal of Inorganic Biochemistry, 180, 1-14. https://doi.org/10.1016/j.jinorgbio.2017.11.025
Skupin-Mrugalska, P., Zalewski, T., Elvang, P. A., Nowaczyk, G., Czajkowski, M., & Stupin-Kempisty, H. (2021). Insight into theranostic nanovesicles prepared by thin lipid hydration and microfluidic method. Colloids and Surfaces B: Biointerfaces, 205, 111871. https://doi.org/10.1016/j.colsurfb.2021.111871
Sonkar, R., Jha, A., Viswanadh, M. K., Burande, A. S., Pawde, D. M., Patel, K. K., Singh, M., Koch, B., & Muthu, M. S. (2021). Gold liposomes for brain-targeted drug delivery: Formulation and brain distribution kinetics. Materials Science and Engineering: C, 120, 111652. https://doi.org/10.1016/j.msec.2020.111652
Zhigaltsev, I. V., Belliveau, N., Hafez, I., Leung, A. K. K., Huft, J., Hansen, C., & Cullis, P. R. (2012). Bottom-up design and synthesis of limit size lipid nanoparticle systems with aqueous and triglyceride cores using millisecond microfluidic mixing. Langmuir, 28(7), 3633-3640. https://doi.org/10.1021/la204833h