Spherical nucleic acids-based nanoplatforms for tumor precision medicine and immunotherapy

Abstract

Precise diagnosis and treatment of tumors currently still face considerable challenges due to the development of highly degreed heterogeneity in the dynamic evolution of tumors. With the rapid development of genomics, personalized diagnosis and treatment using specific genes may be a robust strategy to break through the bottleneck of traditional tumor treatment. Nevertheless, efficient in vivo gene delivery has been frequently hampered by the inherent defects of vectors and various biological barriers. Encouragingly, spherical nucleic acids (SNAs) with good modularity and programmability are excellent candidates capable of addressing traditional gene transfer-associated issues, which enables SNAs a precision nanoplatform with great potential for diverse biomedical applications. In this regard, there have been detailed reviews of SNA in drug delivery, gene regulation, and dermatology treatment. Still, to the best of our knowledge, there is no published systematic review summarizing the use of SNAs in oncology precision medicine and immunotherapy, which are considered new guidelines for oncology treatment. To this end, we summarized the notable advances in SNAs-based precision therapy and immunotherapy for tumors following a classification standard of different types of precise spatiotemporal control on active species by SNAs. Specifically, we focus on the structural diversity and programmability of SNAs. Finally, the challenges and possible solutions were discussed in the concluding remarks. This review will promote the rational design and development of SNAs for tumor-precise medicine and immunotherapy.

Keywords: Immunotherapy; Molecular imaging; Precision medicine; Spherical nucleic acids; Tumor.

Graphical abstract

Scheme 1

Schematic illustration of the diversity of SNA cores, the functions of nucleic acids, and their applications in treating various diseases. (a) The metallic and nonmetallic types of the SNA cores. (b) The detailed functions achieved by SNA surface nucleic acids, including the “carrier” function often used in diagnostic bio-imaging, as well as RNA interference (RNAi) and antisense technology in the field of gene therapy. (c) The typical ways of SNA are used for tumor diagnosis and treatment.

Fig. 1

The typical applications of SNA with metals as the core. (A) The multi-modular structure of SNA as a transport carrier enables accurate multimodal imaging for biomedicine. Reproduced with permission from Ref. [51]. Copyright 2009, Wiley. (B) SNA1 and SNA2 can separately capture the oncogenes miR-21 and miR-155, enabling precision gene therapy. SNA2 can release DOX for precision chemotherapy while capturing miR-155.Then, SNA1 and SNA2 formed aggregates, which increased the retention time of gold nano at the tumor site and improved the efficiency of photothermal treatment. Reproduced with permission from Ref. [57]. Copyright 2022, Wiley. (C) SNAs with a silver core have a more powerful antibacterial effect than a single silver. Reproduced with permission from Ref. [62]. Copyright 2016, Elsevier. (D) SNA based on upconversion nanoparticles performs reversible infrared light modulation of proteins. Reproduced with permission from Ref. [67]. Copyright 2022, Wiley. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Some exquisite examples of SNA with polymers and proteins as functional cores in practical applications. (A) A poly-PR with a bioreducible disulfide bond was used as the core, and the shell was modified with ASO to deregulate the gene for synthesizing tyrosinase. This SNA demonstrates a strong ability to treat skin diseases. Reproduced with permission from Ref. [72]. Copyright 2021, American Chemical Society. (B) The use of PLGA as the core of SNA enables the encapsulation of hydrophobic drugs and the controlled release of the drugs. Reproduced with permission from Ref. [73]. Copyright 2018, Wiley. (C) Nanogel-like SNA not only protects functional nucleic acids from nuclease degradation but also has size-controllable properties. Reproduced with permission from Ref. [75]. Copyright 2018, Wiley. (D) SNA with protein as the core is capable of efficiently transfecting proteins into cells. Reproduced with permission from Ref. [80]. Copyright 2015, American Chemical Society. (E) The conversion of Cas9 proteins into SNA structures through chemical design and synthesis allows efficient access to the nucleus while maintaining the biological activity of Cas9 proteins. This provides a powerful strategy for a wide range of CRISPR-Cas9-based therapeutic applications. Reproduced with permission from Ref. [36]. Copyright 2022, American Chemical Society. (F) Modification of SNA with TfR aptamers enables the delivery of functional proteins across the blood-brain barrier into the brain or CNS. Reproduced with permission from Ref. [81]. Copyright 2022, American Chemical Society.

Fig. 3

Liposomal SNAs and Carrier-free self-delivery SNAs. (A) Liposomal SNA with stable multi-modular structure. Reproduced with permission from Ref. [83]. Copyright 2014, American Chemical Society. (B) FdU is integrated into the gene to form a chemogene, and then two PTXs are modified at the oligonucleotide ends to form a conjugate that self-assembles into an SNA, which has potent anti-tumor effects. Reproduced with permission from Ref. [90]. Copyright 2020, Wiley. (C) The use of thio-modified nucleic acids as carriers for hydrophobic chemotherapeutic drugs has high drug loading rates, and the unloaded portion of the nucleic acid can also be modified with probes or aptamers by Watson-Crick pairing, etc. Reproduced with permission from Ref. [91]. Copyright 2019, Wiley. (D) Co-delivery of siRNA and RAP to atherosclerotic plaques and implementation of synergistic therapy can significantly slow down the progression of atherosclerosis. Reproduced with permission from Ref. [92]. Copyright 2022, Wiley. (E) Self-delivery SNA that encapsulates photosensitizers in a hydrophobic core enable passive targeting of light responsiveness. Reproduced with permission from Ref. [93]. Copyright 2021, American Chemical Society.

Fig. 4

Some common design concepts and applications of SNA-based bio-diagnostics and imaging. (A) Mode of nanoflare and sticky-flare action on fluorescence imaging. Reproduced with permission from Ref. [112]. Copyright 2020, American Chemical Society. (B) Based on fluorescent π-conjugated polymers with light-trapping capability, it enables amplified detection of low concentrations of nucleic acids. Reproduced with permission from Ref. [130]. Copyright 2022, Wiley. (C) Nanoflares can precisely identify microRNAs in tumor exosomes and then combine them with thermophoresis to amplify the sensitivity of the detection. Reproduced with permission from Ref. [138]. Copyright 2020, American Chemical Society.

Fig. 5

The figure shows the precise tumor diagnosis based on biological responsiveness as well as physical stimulus responsiveness. Apart from that, there is also precision imaging of tumors. (A) Designing tumor-specific enzyme-triggered sites in nucleic acid sequences that can specifically identify tumor cells. Reproduced with permission from Ref. [147]. Copyright 2022, American Chemical Society. (B) Schematic of SNA application on theranostics. Reproduced with permission from Ref. [150]. Copyright 2021, American Chemical Society. (C) SNA activated by intracellular specific enzymes is used for the selective regulation of proteins. Reproduced with permission from Ref. [151]. Copyright 2023, Wiley. (D) Photothermal mode modulation within situ targeted photodynamic therapy. Reproduced with permission from Ref. [41]. Copyright 2022, Wiley. (E) Non-invasive imaging of glioblastoma using SNA-transported NIR–II–Emitting Dye. Reproduced with permission from Ref. [157]. Copyright 2022, Wiley. (F) The use of telomerase enables specific diagnostic imaging of tumor cells, overcoming the challenge of precise diagnosis due to tumor heterogeneity. Reproduced with permission from Ref. [158]. Copyright 2018, American Chemical Society.

Fig. 6

SNA's programmable properties enable optimal immunotherapy results. (A) Precise spatial and temporal control of antigen and adjuvant by designing the structural positions of antigen and adjuvant can enhance the immune effect of the SNA vaccine. Reproduced with permission from Ref. [175]. Copyright 2023, Springer Nature. (B) Some of the altered approaches and combinations of options shown in the figure provide robust strategies for the implementation of rational vaccinology. Reproduced with permission from Ref. [179]. Copyright 2022, American Chemical Society.

Fig. 7

Some representative cases of SNA in immune regulation. (A) SNAs with DOX and CpG achieve synergistic functions of chemotherapy and immunotherapy with specific enzymatic activation, which can significantly retard tumor growth. Reproduced with permission from Ref. [192]. Copyright 2022, Springer Nature. (B) The use of vector-free immune SNA with a dual adjuvant can greatly maximize the TLR9 activation effect. Reproduced with permission from Ref. [195]. Copyright 2022, American Chemical Society. (C) Radiotherapy enhances the infiltration accumulation of SNAs, while SNAs act as radiosensitizers and in situ vaccines for tumors, enabling a synergistic treatment strategy of radiotherapy and immunotherapy. Reproduced with permission from Ref. [198]. Copyright 2022, Elsevier B.V. (D) The use of antisense DNA that specifically blocks PD-L1 can effectively block the PD-1/PD-L1 signaling pathway, providing a powerful approach to this precision immunotherapy. Reproduced with permission from Ref. [201]. Copyright 2022, American Chemical Society.