Smart Stimuli-Responsive Nanocarriers: Overcoming Biological Barriers in Solid Tumors

Authors

https://doi.org/10.48314/nna.vi.63

Abstract

Multi-responsive nanocarriers have emerged as a promising platform in precision oncology, offering advanced capabilities for targeted, controlled, and stimuli-adaptive drug delivery. These systems are engineered to respond to multiple endogenous and exogenous stimuli within the Tumor Microenvironment (TME), including pH gradients, redox potential, enzymatic activity, hypoxia, and external physical triggers such as light, ultrasound, and magnetic fields. By integrating these responsive mechanisms, multi-functional nanocarriers can enhance tumor selectivity, improve deep tissue penetration, and enable on-demand drug release, thereby addressing major limitations of conventional chemotherapy and first-generation nanomedicine. Despite significant progress in material design, structural engineering, and preclinical validation, the clinical translation of multi-responsive nanocarriers remains limited. Major challenges include biological barriers such as rapid systemic clearance, abnormal tumor vasculature, elevated Interstitial Fluid Pressure (IFP), dense Extracellular Matrix (ECM), and tumor heterogeneity, as well as issues related to nanocarrier stability, large-scale reproducibility, and regulatory constraints. Additionally, discrepancies between preclinical models and human tumor biology further complicate successful clinical translation. Recent advances in biomimetic engineering, logic-gated delivery systems, and Artificial Intelligence (AI)-assisted nanocarrier design offer promising solutions to overcome these limitations. Furthermore, the development of personalized and multifunctional theranostic platforms is expected to play a key role in improving therapeutic outcomes. Multi-responsive nanocarriers represent a transformative approach in cancer therapy, with strong potential to enable highly precise and patient-specific treatment strategies. Continued interdisciplinary research is essential to bridge the gap between laboratory innovation and clinical application in precision oncology.           

Keywords:

Nanocarriers, Oncology, Tumor microenvironment, Biological barriers, Nanomedicine, Controlled drug release, Cancer therapy

References

  1. [1] Basety, S., Gudepu, R., & Velidandi, A. (2026). Smart nanoformulations for oncology: A review on overcoming biological barriers with active targeting, stimuli-responsive, and controlled release for effective drug delivery. Pharmaceutics, 18(2), 196. https://doi.org/10.3390/pharmaceutics18020196
  2. [2] Zhao, X., Bai, J., & Yang, W. (2021). Stimuli-responsive nanocarriers for therapeutic applications in cancer. Cancer biology & medicine, 18(2), 319–335. 10.20892/j.issn.2095-3941.2020.0496
  3. [3] Tapeh, S. M. T., Baei, M. S., & Keshel, S. H. (2021). Synthesis of thermogel modified with biomaterials as carrier for hUSSCs differentiation into cardiac cells: Physicomechanical and biological assessment. Materials science and engineering: c, 119, 111517. https://doi.org/10.1016/j.msec.2020.111517
  4. [4] Fathi, M., Abdolahinia, E. D., Barar, J., & Omidi, Y. (2020). Smart stimuli-responsive biopolymeric nanomedicines for targeted therapy of solid tumors. Nanomedicine, 15(22), 2171–2200. https://doi.org/10.2217/nnm-2020-0146
  5. [5] Chenab, K. K., Malektaj, H., Nadinlooie, A. A. R., Mohammadi, S., & Zamani-Meymian, M.-R. (2024). Intertumoral and intratumoral barriers as approaches for drug delivery and theranostics to solid tumors using stimuli-responsive materials. Microchimica acta, 191(9), 541. https://doi.org/10.1007/s00604-024-06583-y
  6. [6] Sabir, F., Zeeshan, M., Laraib, U., Barani, M., Rahdar, A., Cucchiarini, M., & Pandey, S. (2021). DNA based and stimuli-responsive smart nanocarrier for diagnosis and treatment of cancer: Applications and challenges. Cancers, 13(14), 3396. https://doi.org/10.3390/cancers13143396
  7. [7] Majumder, J., & Minko, T. (2021). Multifunctional and stimuli-responsive nanocarriers for targeted therapeutic delivery. Expert opinion on drug delivery, 18(2), 205–227. https://doi.org/10.1080/17425247.2021.1828339
  8. [8] Mohamed, R. G. A., Ali, S. M., Ahmed, I. S., Rawas-Qalaji, M., & Hussain, Z. (2025). Next-generation nanocarriers for colorectal cancer: passive, active, and stimuli-responsive strategies for precision therapy. Biomaterials science, 13(20), 5626–5664. https://doi.org/10.1039/D5BM01176K
  9. [9] Murugan, B., Sagadevan, S., Fatimah, I., Oh, W. C., Motalib Hossain, M. A., & Johan, M. R. (2021). Smart stimuli-responsive nanocarriers for the cancer therapy--nanomedicine. Nanotechnology reviews, 10(1), 933–953. https://doi.org/10.1515/ntrev-2021-0067
  10. [10] Du, J., Lane, L. A., & Nie, S. (2015). Stimuli-responsive nanoparticles for targeting the tumor microenvironment. Journal of controlled release, 219, 205–214. https://doi.org/10.1016/j.jconrel.2015.08.050
  11. [11] Kaushik, N., Borkar, S. B., Nandanwar, S. K., Panda, P. K., Choi, E. H., & Kaushik, N. K. (2022). Nanocarrier cancer therapeutics with functional stimuli-responsive mechanisms. Journal of nanobiotechnology, 20(1), 152. https://doi.org/10.1186/s12951-022-01364-2
  12. [12] Baniasad, A., Baei, M. S., & Tala-Tapeh, S. M. (2025). Chitosan-PEGylated niosomes and liposomes as biomacromolecule carriers for Alzheimer’s disease treatment: Galantamine drug delivery carrier. Materials chemistry and physics, 352, 132003. https://doi.org/10.1016/j.matchemphys.2025.132003
  13. [13] Qiao, Y., Wan, J., Zhou, L., Ma, W., Yang, Y., Luo, W., … & Wang, H. (2019). Stimuli-responsive nanotherapeutics for precision drug delivery and cancer therapy. Wiley interdisciplinary reviews: nanomedicine and nanobiotechnology, 11(1), e1527. https://doi.org/10.1002/wnan.1527
  14. [14] Kasiński, A., Zielińska-Pisklak, M., Oledzka, E., & Sobczak, M. (2020). Smart hydrogels--synthetic stimuli-responsive antitumor drug release systems. International journal of nanomedicine, 15, 4541–4572. https://doi.org/10.2147/ijn.s248987
  15. [15] Thomas, R. G., Surendran, S. P., & Jeong, Y. Y. (2020). Tumor microenvironment-stimuli responsive nanoparticles for anticancer therapy. Frontiers in molecular biosciences, 7, 610533. https://doi.org/10.3389/fmolb.2020.610533
  16. [16] Shishir, M. R. I., Gowd, V., Suo, H., Wang, M., Wang, Q., Chen, F., & Cheng, K.-W. (2021). Advances in smart delivery of food bioactive compounds using stimuli-responsive carriers: Responsive mechanism, contemporary challenges, and prospects. Comprehensive reviews in food science and food safety, 20(6), 5449–5488. https://doi.org/10.1111/1541-4337.12851
  17. [17] Fang, Z., Shen, Y., & Gao, D. (2021). Stimulus-responsive nanocarriers for targeted drug delivery. New journal of chemistry, 45(10), 4534–4544. https://doi.org/10.1039/D0NJ05169A
  18. [18] Zuo, H., Jiao, Y., Chen, J., Tong, S., Li, Y., & Zhao, W. (2026). Recent advances in smart stimulus-responsive hydrogels for precision drug delivery in tumours. Gels, 12(2), 98. https://doi.org/10.3390/gels12020098
  19. [19] Mi, P. (2020). Stimuli-responsive nanocarriers for drug delivery, tumor imaging, therapy and theranostics. Theranostics, 10(10), 4557. https://doi.org/10.7150/thno.38069
  20. [20] Niknejad, K., Sharifzadeh Baei, M., & Motallebi Tala Tapeh, S. (2018). Synthesis of metformin hydrochloride nanoliposomes: Evaluation of physicochemical characteristics and release kinetics. International journal of nano dimension, 9(3), 298–313. https://ijnd.tonekabon.iau.ir/article_659887.html
  21. [21] Ukidve, A., Cu, K., Kumbhojkar, N., Lahann, J., & Mitragotri, S. (2021). Overcoming biological barriers to improve solid tumor immunotherapy. Drug delivery and translational research, 11(6), 2276–2301. https://doi.org/10.1007/s13346-021-00923-8
  22. [22] Asadi, K., Samiraninezhad, N., Akbarizadeh, A. R., Amini, A., & Gholami, A. (2024). Stimuli-responsive hydrogel based on natural polymers for breast cancer. Frontiers in chemistry, 12, 1325204. https://doi.org/10.3389/fchem.2024.1325204
  23. [23] Motallebi, S. (2025). Advances in Mesoporous silica nanoparticles for targeted and controlled drug delivery. Biocompounds, 2(4), 212–225. https://doi.org/10.48313/bic.v2i4.49

Downloads

Published

2026-06-07

Issue

Vol. 1 No. 2 (2026): Nano Nexus & Applications (NNA)

Section

Articles

Categories

How to Cite

Motallebi, S. . (2026). Smart Stimuli-Responsive Nanocarriers: Overcoming Biological Barriers in Solid Tumors. Nano Nexus & Applications, 1(2), 67-81. https://doi.org/10.48314/nna.vi.63