Construction of Nanocarriers Based on Nucleic Acids and Their Applications in Nanobiology Delivery Systems

Purpose: Cancer treatment still relies heavily on chemotherapy, which causes severe damage to normal cells and systemic side effects. Safer, more selective drug delivery strategies are needed. Nanocarriers based on nucleic acids (NCNAs) are attractive because nucleic acids offer biocompatibility, low toxicity, programmable structures, controllable size, and modifiability—advantages that address limitations of cationic polymers, dendrimers, and inorganic nanoparticles. ---

Hypothesis: The review’s central thesis is: if nucleic acid nanostructures are constructed through strict complementary base pairing and functionalized with targeting ligands, therapeutic nucleic acids, drugs, or logic elements, then NCNAs can enable precise targeted delivery, biosensing, gene silencing, vaccine transport, phototherapy, and logic-gated diagnostics with low toxicity and high programmability. ---

Aims: - Review DNA nanocarriers, including self-assembled DNA and DNA-decorated nanoparticles. - Review RNA nanocarriers, including self-assembled RNA and RNA-decorated nanoparticles. - Review DNA/RNA hybrid nanocarriers and their construction. - Summarize biological applications of functionalized NCNAs: biosensing/bioimaging, cargo loading and transport (chemotherapy drugs, genes, vaccines, photosensitizers, codrugs), and diagnostic logic gates. - Provide perspectives on future directions and challenges. ---

Delivery system: Nucleic acid-based nanocarriers (NCNAs): - DNA nanocarriers: self-assembled DNA tetrahedra, DNA prisms, DNA nanocages, spherical nucleic acids (SNAs), DNA nanogels, DNA origami; DNA-decorated nanoparticles (gold, magnetic, MoS₂, hollow mesoporous silica). - RNA nanocarriers: self-assembled RNA, RNA nanoflowers, RNA-decorated nanoparticles (Se/Ru metal–organic frameworks, carbonate apatite, magnetic nanoparticles, PEG, carbon nanospheres, peptides, proteins). - DNA/RNA hybrid nanocarriers: DNA dendrimer + siRNA, spherical nucleic acids with grafted siRNA, DNA/RNA nanocapsules, DNA nanorobots + gold nanoparticles + RNA. Targeting ligands: aptamers (e.g., AS1411, cyclic bivalent aptamers, bifunctional aptamers), folic acid, transferrin, peptides, proteins, antibodies. Payloads: chemotherapy drugs (DOX, gemcitabine, 5-fluorouracil, paclitaxel), siRNA, mRNA, miRNA, antisense oligonucleotides, vaccines/neoantigens, CpG adjuvants, photosensitizers (Ce6, ICG, porphyrins), codrugs. Logic elements: aptamer-based AND/OR gates, toehold switches, hybridization chain reaction, ATP-responsive SNA gels. ---

Approach: Narrative review of published literature. Model systems discussed include: - In vitro cell lines: CEM, Ramos, HeLa, MCF-7, and others. - In vivo models: tumor-bearing mice, orthotopic glioblastoma, breast tumor, melanoma, and other cancer models. - Disease context: cancer therapy, gene silencing, immunotherapy, photodynamic therapy (PDT), photothermal therapy (PTT), vaccine delivery, biosensing. - No primary experimental groups: the article synthesizes and interprets published studies. ---

Key methods: Techniques highlighted across cited studies: - Flow cytometry for cellular drug uptake and cytotoxicity. - Confocal fluorescence imaging for intracellular tracking and bioimaging. - In vivo tumor growth inhibition and survival analysis. - H&E staining, TUNEL apoptosis assay, cleaved caspase 3, proliferation, and PLK1 staining for biosafety/efficacy. - Gel electrophoresis, self-assembly characterization, and nanoparticle tracking (implied across cited works). - Logic-gate operation via strand displacement, enzyme cleavage, and aptamer recognition. ---

Key results: - DNA tetrahedron loaded with 5-fluorouracil: after 12 h co-incubation, the percentage of drug in cells was nearly 40%, demonstrating stable and efficient drug delivery. - DNA/RNA hybrid spherical nucleic acid with siRNA: rapidly absorbed by more than 60 kinds of cells; protected siRNA from enzymatic digestion and released it upon intracellular Dicer cleavage. - Se/Ru metal–organic nanoparticles + siRNA: enhanced cell uptake and promoted siRNA escape from endosomes/lysosomes, producing synergistic cancer cell killing. - Carbonate apatite nanoparticles + siRNA: stronger cytotoxicity than nanoparticles alone in cell activity assays; satisfactory in vivo and in vitro results. - FA/MNP/RNA nanoflowers + DOX + photosensitizer: high selectivity and stability, protected RNA from degradation, and enabled cancer cell detection and combined therapy. ---

Interpretation: The authors claim that NCNAs are powerful, novel nanocarriers with good biocompatibility, low toxicity, programmable structures, controllable size, and modifiability. They conclude that NCNAs have great potential in biosensing, targeted drug/gene/vaccine delivery, phototherapy, counteracting drug resistance, and logic-gated diagnostics, and that they are promising for precision medicine. However, clinical translation remains early and requires deeper understanding of nucleic acid characteristics and NCNA behavior. ---

Limitations: - Complex NCNA structures make in vivo effects difficult to predict. - Pharmacokinetics—circulation, excretion, and decomposition—are not fully understood. - Physicochemical properties such as surface charge and geometry require further study. - Nanocarriers generally rely on endocytosis; dynamic cellular changes can alter uptake and targeting. - Reducing non-selective uptake by certain organs and cells remains a challenge. - RNA instability in blood requires protective carrier design. - Clinical practice is still in early stages; long-term biosafety and scale-up manufacturing need further development.