Engineering spherical nucleic acids for precision cancer therapy: design strategies and medical applications

Malignant tumor treatment still faces issues like insufficient targeting, drug resistance, and immunosuppression. Spherical nucleic acids (SNAs), with their three-dimensional core-shell structure and densely packed, radially oriented oligonucleotide shell, enable transfection-free cellular uptake and provide nuclease resistance and stability. This review examines SNA engineering strategies and their impact on precision oncology. Functionalization with antibodies, aptamers, or antisense oligonucleotides enables SNAs to target key molecules such as human epidermal growth factor receptor 2 (HER2), programmed death-ligand 1 (PD-L1), and toll-like receptors (TLRs). Advances in stimuli-responsive, self-assembled, liposomal, and peptide-based carrier systems facilitate controlled drug release and modulation of the tumor microenvironment (TME). Diagnostic applications of SNAs include electrochemical, fluorescent, and colorimetric sensing systems for detecting biomarkers such as exosomes, miRNAs, alpha-methylacyl-CoA racemase (AMACR), and telomerase. Therapeutically, SNAs co-deliver chemotherapeutics and immunoadjuvants, support cancer vaccines, and exert efficacy in various tumors, including the central nervous, reproductive, digestive, hematological, barrier, and respiratory systems. Early clinical studies indicate a favorable biosafety profile, but issues remain regarding delivery efficiency, target selectivity, scalability, and long-term safety. Progress toward biodegradable, machine-learning-guided SNA platforms may soon make this nanotechnology a fundamental part of personalized, precision cancer medicine.