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  • Electro-Ionic Tumor Microenvironment as a Design Cue for Engineering Smart Drug Delivery Systems

  • Niloofar Allamehzadeh,1 Sadaf Vahdat,2,* Azar Rezaei,3
    1. Faculty of Interdisciplinary Science and Technology, Tarbiat Modares University
    2. Applied Cell Sciences Division, Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
    3. Faculty of Interdisciplinary Science and Technology, Tarbiat Modares University


  • Introduction: The tumor microenvironment (TME) is characterized not only by biochemical abnormalities but also by altered ionic and bioelectric properties that influence cancer cell signaling, proliferation, migration, and therapeutic response. Dysregulation of ions, such as H⁺, Na⁺, K⁺, Ca²⁺, and Cl⁻, together with changes in ionic strength, membrane potential, and ion-channel activity, provides an emerging set of physicochemical cues that may be exploited for precision drug delivery. Hydrogels, owing to their high water content, tunable network properties, and biocompatibility, offer a suitable platform for integrating such responsiveness into localized and controlled therapeutic systems. This review aimed to classify the major electro-ionic features of the TME relevant to drug delivery, examine strategies for converting these features into endogenous or externally controlled release mechanisms, and evaluate the potential of conductive and electroactive hydrogels for on-demand cancer therapy.
  • Methods: Published studies on the electrical and ionic characteristics of the TME, ion homeostasis in cancer, stimuli-responsive hydrogels, conductive polymers, and electroresponsive drug delivery systems were reviewed. Relevant cues were categorized into ionic stimuli (pH/proton concentration, ionic strength, and dysregulated Na⁺, K⁺, Ca²⁺, and Cl⁻ homeostasis), bioelectric features (membrane potential, ion-channel activity, and endogenous electrical gradients), and externally applied electrical stimuli. Corresponding material strategies were classified into ion-sensitive hydrogels, ionic and polyelectrolyte networks, conductive polymer-based hydrogels, and electroactive systems capable of electrically controlled drug release.
  • Results: The reviewed evidence showed that electro-ionic characteristics can influence hydrogel swelling, charge interactions, ion exchange, molecular transport, and drug-matrix interactions, providing multiple opportunities for responsive drug delivery. Ionic and pH-sensitive networks can exploit local changes in proton concentration and ionic conditions to modulate network properties and drug release. Conductive hydrogels can provide ionic and/or electronic conductivity and enable electrically controlled release through mechanisms involving electrochemical reactions, ion migration, and changes in polymer charge state. Externally applied electrical fields further provide an additional level of temporal control, allowing drug release to be triggered or modulated on demand. These strategies may be particularly valuable for localized delivery, combination therapies, and systems requiring spatial or temporal control of therapeutic exposure.
  • Conclusion: The electro-ionic TME represents an underexploited design space for smart drug delivery. Integrating ionic responsiveness, conductive networks, and externally controlled electrical stimulation may enable next-generation hydrogels with programmable drug release. Future development should focus on quantitative characterization of tumor-specific ionic and electrical parameters, precise control of electrochemical responses, reproducible fabrication, long-term biocompatibility, and validation in physiologically relevant tumor models.
  • Keywords: Tumor Microenvironment; Bioelectric Cues; Ionic Homeostasis; Conductive Hydrogels

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