Extracellular vesicle-mimetic nanogels: overcoming barriers in advanced breast cancer

Breast cancer remains one of the most common malignancies among women worldwide. Conventional treatment strategies including surgery, adjuvant/neoadjuvant chemotherapy, and targeted therapies, are often associated with severe side effects, poor selectivity, low drug solubility, and high recurrence rates. Nanogel-based drug delivery systems have emerged as promising platforms in precision oncology due to their ability to enhance drug solubility, improve bioavailability, and facilitate targeted delivery through enhanced permeability and retention (EPR) effects. This review focuses on stimuli-responsive nanogels, including pH-, redox (GSH)-, enzyme-, temperature-, and light-responsive systems, and highlights their application in breast cancer therapy. Their design, synthesis, drug loading efficiency, and controlled release mechanisms within the tumor microenvironment are discussed. Preclinical studies demonstrate improved cytotoxicity against various breast cancer cell lines, inhibition of metastasis via EPR-mediated accumulation, and synergy with immunotherapy and chemotherapy combinations. Dual- and multi-responsive nanogels enable theranostic applications, including real-time imaging and localized payload delivery to overcome multidrug resistance. Despite promising results, challenges persist in clinical translation, including nanogel stability, immunogenicity, scalability, and the lack of long-term safety data from ongoing clinical trials (e.g., NCT identifiers). This review synthesizes mechanistic insights, comparative efficacy data, and regulatory hurdles, and advocates for interdisciplinary efforts to advance nanogels towards personalized breast cancer management.