Redox-Responsive Theranostic Nanoplatforms in Oncology: Linking Tumor Microenvironment Biology, Proteasome Targeting, and Clinical Translation

Theranostic nanoparticles, which integrate diagnostic imaging and therapeutic delivery within a single nanoplatform, represent a transformative paradigm in oncological nanomedicine. Despite substantial preclinical progress, the field faces persistent gaps in rational nanoparticle design informed by tumor biology, preclinical model fidelity, and clinical translation. This review critically synthesizes theranostic nanoparticle research across three underexplored domains. First, we examine tumor microenvironment features—reactive oxygen species dynamics, glutathione gradients, hypoxia, and proteasomal dysregulation—as mechanistic drivers of nanoparticle responsiveness. Second, we evaluate redox-responsive and proteasome-targeted nanoplatforms that exploit these cues for stimuli-triggered drug release and simultaneous imaging readout. Third, we address the unmet need for three-dimensional organoid and microfluidic tumor models as predictive preclinical testing environments, given the well-documented limitations of conventional two-dimensional cultures. Cancer subtype-specific applications are discussed for breast cancer, HPV-associated malignancies, colorectal cancer, and prostate cancer. Clinical translation barriers—including pharmacokinetic constraints, protein corona formation, immune clearance, anti-PEG antibodies, complement activation-related pseudoallergy, and FDA/EMA regulatory pathways—are addressed from a clinical oncology perspective. The review concludes with a research roadmap integrating proteomics-guided nanoparticle engineering, patient-derived organoid biobanks, and artificial intelligence-assisted design as priority areas for next-generation oncological theranostics.