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  4. Vol 7, Issue 2, 2026

Tumor Microenvironment-Responsive Nanoparticles for Cancer Therapy: Design Strategies and Recent Advances

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DOI: 10.23977/medsc.2026.070202 | Downloads: 2 | Views: 104

Author(s)

Xiaowei Chang 1, Jinjin Liu 1, Shasha Jiang 1

Affiliation(s)

1 Yan'an Medical College of Yan'an University, Yan'an, 716000, China

Corresponding Author

Xiaowei Chang

ABSTRACT

The tumor microenvironment (TME) plays a critical role in cancer progression and therapeutic resistance and is characterized by features such as hypoxia, acidic pH, aberrant enzyme expression, and redox imbalance. These characteristics provide endogenous stimuli for the development of stimulus-responsive nanomedicine. TME-responsive nanoparticles can recognize specific physicochemical signals within tumor tissues, enabling targeted drug delivery and controlled release, thereby enhancing therapeutic efficacy while reducing systemic toxicity. This review summarizes recent advances in the design and application of TME-responsive nanoparticles, focusing on hypoxia-, pH-, enzyme-, and redox-responsive nanoplatforms. Their roles in multimodal synergistic therapy and the induction of regulated cell death are also discussed. Finally, current challenges related to biosafety, in vivo stability, and clinical translation are highlighted to provide insights for the future development of TME-responsive nanomedicine.

KEYWORDS

Tumor microenvironment, Stimuli-responsive nanoparticles, Nanomedicine

CITE THIS PAPER

Xiaowei Chang, Jinjin Liu, Shasha Jiang, Tumor Microenvironment-Responsive Nanoparticles for Cancer Therapy: Design Strategies and Recent Advances. MEDS Clinical Medicine (2026). Vol. 7, No.2, 6-13. DOI: http://dx.doi.org/10.23977/medsc.2026.070202.

REFERENCES

[1] GAREMILLA S S S, GAMPA S C, GARIMELLA S. Role of the tumor microenvironment in cancer therapy: unveiling new targets to overcome drug resistance[J]. Medical Oncology, 2025, 42(6): 202.
[2] WICKS E E, SEMENZA G L. Hypoxia-inducible factors: cancer progression and clinical translation[J]. The Journal of Clinical Investigation, 132(11): e159839.
[3] CHEN Z, HAN F, DU Y, et al. Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions[J]. Signal Transduction and Targeted Therapy, 2023, 8: 70.
[4] JIANG J, JIN L, ZHAO Z, et al. Design and application of proton gradient-based pH-responsive nanomaterials in the tumor microenvironment[J]. Nanoscale, 2025, 17(47): 27042-27065.
[5] GUO F, DU Y, WANG Y, et al. Targeted drug delivery systems for matrix metalloproteinase-responsive nanoparticles in tumor cells: a review[J]. International Journal of Biological Macromolecules, 2024, 257: 128658.
[6] THAMBI T, PARK J H, LEE D S. Hypoxia-responsive nanocarriers for cancer imaging and therapy: recent approaches and future perspectives[J]. Chemical Communications, 2016, 52(55): 8492-8500.
[7] CHEN G, WU K, LI H, et al. Role of hypoxia in the tumor microenvironment and targeted therapy[J]. Frontiers in Oncology, 2022, 12: 961637.
[8] EL-TANANI M, RABBANI S A, BABIKER R, et al. Unraveling the tumor microenvironment: insights into cancer metastasis and therapeutic strategies[J]. Cancer Letters, 2024, 591: 216894.
[9] KWON Y, KIM M, KIM Y, et al. Exosomal MicroRNAs as mediators of cellular interactions between cancer cells and macrophages[J]. Frontiers in Immunology, 2020, 11: 1167.
[10] ZHANG M, XU H, WU X, et al. Engineering dual-responsive nanoplatform achieves copper metabolism disruption and glutathione consumption to provoke cuproptosis/ferroptosis/apoptosis for cancer therapy[J]. ACS Applied Materials & Interfaces, 2025, 17(14): 20726-20740.
[11] MUVAKIT S. The role of free radicals and oxidative stress in chronic diseases: a comprehensive review of mechanisms and therapeutic interventions[J]. Journal of Health, Medicine and Nursing, 2025, 119: 60.
[12] DONG Y, XU C, GUO J, et al. Advances in ferroptosis of cancer therapy[J]. Oncologie, 2024, 26(1): 1-8.
[13] BRANDL N, SEITZ R, SENDTNER N, et al. Living on the edge: ROS homeostasis in cancer cells and its potential as a therapeutic target[J]. Antioxidants, 2025, 14(8): 1002.
[14] KARIMI S, BAKHSHALI R, BOLANDI S, et al. For and against tumor microenvironment: nanoparticle-based strategies for active cancer therapy[J]. Materials Today Bio, 2025, 31: 101626.
[15] JEDLIČKA M, FEGLAROVÁ T, JANSTOVÁ L, et al. Lactate from the tumor microenvironment - a key obstacle in NK cell-based immunotherapies[J]. Frontiers in Immunology, 2022, 13: 932055.
[16] SUN H, LI Y, XUE M, et al. Tumor microenvironment-responsive nanoparticles: promising cancer PTT carriers[J]. International Journal of Nanomedicine, 2025, 20: 7987-8001.
[17] MIR R, JAVID J, ULLAH M F, et al. Metabolic reprogramming and functional crosstalk within the tumor microenvironment (TME) and a multi-omics anticancer approach[J]. Medical Oncology, 2025, 42(9): 373.
[18] NILAND S, RISCANEVO A X, EBLE J A. Matrix metalloproteinases shape the tumor microenvironment in cancer progression[J]. International Journal of Molecular Sciences, 2021, 23(1): 146.
[19] BEAUPRE D M, WEISS R G. Thiol- and disulfide-based stimulus-responsive soft materials and self-assembling systems[J]. Molecules, 2021, 26(11).
[20] ZHANG W, GE L, ZHANG Y, et al. Targeted intervention of tumor microenvironment with HDAC inhibitors and their combination therapy strategies[J]. European Journal of Medical Research, 2025, 30(1): 69.
[21] KUMARI R, SUNIL D, NINGTHOUJAM R S. Hypoxia-responsive nanoparticle based drug delivery systems in cancer therapy: an up-to-date review[J]. Journal of Controlled Release, 2020, 319: 135-156.
[22] LI Y, JEON J, PARK J H. Hypoxia-responsive nanoparticles for tumor-targeted drug delivery[J]. Cancer Letters, 2020, 490: 31-43.
[23] XIA Y, DUAN S, HAN C, et al. Hypoxia-responsive nanomaterials for tumor imaging and therapy[J]. Frontiers in Oncology, 2022, 12.
[24] FENG H, CHU D, YANG F, et al. Hypoxia-responsive polymeric micelles for enhancing cancer treatment[J]. Frontiers in Chemistry, 2020, 8.
[25] THAMBI T, DEEPAGAN V G, YOON H Y, et al. Hypoxia-responsive polymeric nanoparticles for tumor-targeted drug delivery[J]. Biomaterials, 2014, 35(5): 1735-1743.
[26] SUN H, LI X, LIU Q, et al. pH-responsive self-assembled nanoparticles for tumor-targeted drug delivery[J]. Journal of Drug Targeting, 2024, 32(6): 672-706.
[27] YAO Y, SAW P E, NIE Y, et al. Multifunctional sharp pH-responsive nanoparticles for targeted drug delivery and effective breast cancer therapy[J]. Journal of Materials Chemistry B, 2019, 7(4): 576-585.
[28] LIU N, REN X, GUO W, et al. Microwave-responsive, energy-metabolism-regulating nanosystem for tumor treatment through co-promotion of cuproptosis/ferroptosis[J]. Journal of Colloid and Interface Science, 2026, 704: 139424.
[29] LI J, LIAO H, TIAN S, et al. A pH-responsive polycarbonate nanoplatform enables sequential drug release for enhanced apoptotic cascade synergy in non-small cell lung cancer therapy[J]. Acta Biomaterialia, 2025, 205: 550-567.
[30] LI J, SHANG W, LI Y, et al. Advanced nanomaterials targeting hypoxia to enhance radiotherapy[J]. International Journal of Nanomedicine, 2018, 13: 5925-5936.
[31] YIN R, GUO Z, LV X, et al. Intracellular delivery of mitochondria-targeting cationic polypeptides by pH-responsive nanoparticles to induce immunogenic cell death[J]. Biomacromolecules, 2025, 26(11): 7564-7575.
[32] YUN K, YU X, LIANG S, et al. Tumor-responsive cuproptosis nanoinducer realizing efficient PANoptosis for enhanced cancer immunotherapy[J]. Theranostics, 2025, 15(17): 9294-9305.
[33] YANG D C, ZHUANG H, ZHENG J, et al. Hypoxia-responsive nano-photosensitizer anchored by PEGylated BODIPY: a single-laser-driven platform for photo-enhanced synergistic chemo/photodynamic/photothermal cancer therapy[J]. Molecular Pharmaceutics, 2025, 22(9): 5603-5615.
[34] DEBNATH S K, DEBNATH M, GHOSH A, et al. Targeting tumor hypoxia with nanoparticle-based therapies: challenges, opportunities, and clinical implications[J]. Pharmaceuticals, 2024, 17(10): 1389.
[35] ZHU G, QIAN Y, GAO M, et al. A novel nano-biocomposite synergistically activates PANoptosis and cGAS-STING for precise cancer immunotherapy[J]. Biomaterials, 2026, 327: 123758.
[36] DEIRRAM N, ZHANG C, KERMANIYAN S S, et al. pH-responsive polymer nanoparticles for drug delivery[J]. Macromolecular Rapid Communications, 2019, 40(10): 1800917.
[37] FARSANI N K, AFSHARI S, POOR A S, et al. pH-responsive mesoporous silica nanoparticles functionalized with folic acid and chitosan for targeted epirubicin delivery: In vitro and in vivo efficacy in breast cancer[J]. International Journal of Biological Macromolecules, 2025, 309: 142558.
[38] LING B, WANG Y, DONG H, et al. Enzyme-triggered aggregation of upconversion nanoparticles for targeted photodynamic therapy via NIR irradiation[J]. Nanoscale Advances, 7(10): 3068-3076.
[39] RICHARDS B A, YEAGER L P, SULLIVAN M O, et al. Leveraging endogenous MMPs for drug delivery in the cancer environment[J]. Expert Opinion on Drug Delivery, 2025, 22(10): 1527-1539.
[40] CHEN Y, CHEN Q, MA Y, et al. Cathepsin B-ignited nanorocket to blast tumor lysosomes for TLR-fortified lysosomal immunotherapy with dual-switchable fluorescence/magnetic resonance imaging[J]. Journal of the American Chemical Society, 2025, 147(28): 24884-24899.
[41] SHI H, XIE Z, ZHANG J, et al. Cu-doped dendritic biodegradable nanoplatforms for augmenting cuproptosis and tumor-starvation therapy through mitochondrial metabolic cascade modulation[J]. Materials Today Bio, 2025, 35: 102477.
[42] LI M, ZHAO G, SU W K, et al. Enzyme-responsive nanoparticles for anti-tumor drug delivery[J]. Frontiers in Chemistry, 2020, 8: 647.
[43] LUO Z, CAI K, HU Y, et al. Redox-responsive molecular nanoreservoirs for controlled intracellular anticancer drug delivery based on magnetic nanoparticles[J]. Advanced Materials, 2012, 24(3): 431-435.
[44] WANG L, DENG Y, ZHOU X, et al. A biodegradable nanomedicine for potentiated cancer therapy via Ca2+-overload and photothermal dual-amplifying cuproptosis[J]. Journal of Colloid and Interface Science, 2026, 705: 139548.
[45] YANG P, ZHANG J, CHANG Y, et al. Tumor microenvironment responsive smart nanoplatform for synergistic tumor therapy through co-enhancement of GSH depletion and hypoxia relief[J]. Journal of Inorganic Biochemistry, 2025, 272: 113005.
[46] SUN Y, WANG S, LIU J, et al. Tailoring modification modules of paclitaxel prodrug nanoassemblies to manipulate efficacy and tolerance[J]. Nano Today, 2024, 56: 102275.
[47] JEON J, YOON B, DEY A, et al. Self-immolative polymer-based immunogenic cell death inducer for regulation of redox homeostasis[J]. Biomaterials, 2023, 295: 122064.
[48] WEI P, NIU X, WANG D, et al. A glutathione-responsive ferroptotic inducer with elevated labile iron pool and self-supplied peroxide for chemodynamic therapy[J]. Materials Today Bio, 2025, 32: 101913.
[49] CHEN X, JI J, LI S, et al. Synergistic enhancement of ferroptosis via a multi-functional metal-coordinated nanoplatform for cancer therapy[J]. Colloids and Surfaces B: Biointerfaces, 2026, 258: 115205.
[50] JIANG C, LI X, WAN S, et al. Copper-doped polydopamine nanoparticles-mediated GSH/GPX4-depleted ferroptosis and cuproptosis sensitizes lung tumor to checkpoint blockade immunotherapy[J]. Small, 2025, 21(23): e2503208.
[51] CHEN H, ZHENG G, QIN F, et al. Assembled gold superstructure triggered synergistic apoptosis/ferroptosis via combined photo-enzyme therapy[J]. ACS applied materials & interfaces, 2025, 17(50): 68345-68363.

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