Intelligent CpG nanoplatforms for targeted cancer immunotherapy and immune remodeling

CpG oligonucleotides are potent immunoadjuvants that hold great promise for cancer immunotherapy, but their clinical use is limited by in vivo instability, off-target toxicity, and poor tumor targeting. Intelligent nanoplatforms offer effective solutions to these challenges by protecting CpG, improving delivery precision, and enabling on-demand cargo release. This review summarizes four major design strategies: biomimetic/biohybrid systems for targeted delivery, stimuli-responsive nanocarriers for controlled release, structural engineering for enhanced immune activation, and combinatorial therapy for systemic immune remodeling. These nanoplatforms not only improve CpG stability and tumor-targeting capability but also reshape the tumor immune microenvironment, convert "cold" tumors to "hot" phenotypes, and induce long-term immune memory. We highlight the design principles, action mechanisms, key advantages, and inherent limitations of current intelligent CpG-based nanosystems, aiming to advance the development and clinical translation of CpG nanotherapeutics for more effective and personalized cancer immunotherapy.