Injectable Hydrogels for Breast Cancer Therapy: From Tumor Microenvironment-Responsive and Actively Targeted Drug Delivery to Immunotherapy and Theranostics

Abstract

Breast cancer treatment still faces challenges including local recurrence, systemic toxicity, tumor heterogeneity, drug resistance, and immunosuppression. Conventional systemic administration provides limited exposure at the tumor site and exhibits significant toxicity. Injectable hydrogels, combining the properties of minimally invasive administration, in situ gelation, local retention, and sustained release, have become a key platform for local precision drug delivery. Compared with nanomedicines or free drugs, hydrogels can both prolong drug retention time and achieve on-demand release through the modulation of crosslinking density, degradation rate, and responsive chemical bonds. This review is organized around the material logic of such systems. Injectable hydrogels are first classified into natural, synthetic, hybrid, supramolecular, nanocomposite, and self-healing systems, the in situ gelation chemistries available to each are compared, and network parameters such as crosslinking density, mesh size, swelling, porosity, modulus, and rheology are related to release kinetics and intratumoral retention. Current research is primarily advancing along two directions: one is the construction of pH-, enzyme-, redox/ROS-, hypoxia-, ATP-, glucose-or thermo-responsive hydrogels; the other is achieving active targeting by integrating functionalized hydrogels with targets such as CD44, folate receptor, integrins, EGFR, transferrin receptor, and HER2 or with biomimetic cell-membrane coatings. On this basis, hydrogels have been extended to cancer vaccines, immune checkpoint modulation, local delivery of CAR-T/CAR-NK, as well as combination therapies involving chemotherapy, photothermal therapy, photodynamic therapy, chemodynamic therapy, sonodynamic therapy, radiosensitization, gene therapy, and theranostics. The constraints imposed on hydrogel design by different payload classes, including small molecules, natural products, proteins and peptides, nucleic acids, antibodies, exosomes, and gene-editing machinery, are further examined, and imaging-integrated theranostic gels are discussed together with the emerging role of machine learning and digital fabrication in hydrogel optimization. Based on the biological foundations of breast cancer, this review summarizes advances in the material design, microenvironment-responsive release, targeting strategies, immunomodulation, and combination therapy of hydrogels, critically evaluates the limitations of each strategy, and aims to provide a reference for the design of mechanistically well-defined and translatable hydrogel delivery systems for breast cancer.