Future
1. Conformational change.
We aim to determine the irradiation time and power that can ensure conformational changes in Doara without damaging its structure or causing an overall solution temperature increase.
We will modify Doara with Cy5 (fluorophores) and BHQ-2 (quenchers) to monitor the conformational changes.[1] Additionally, we will use transmission electron microscope (TEM) to ascertain the integrity of Doara after irradiation.
2. Doara in vivo.
We will investigate Doara's stability and functionality under physiological pH and Mg2+ concentrations. Subsequently, we will determine cytotoxicity using cell experiments, followed by animal experiments to assess hepatotoxicity, immunogenicity, and plasma stability. [2]
3. Cargo loading and phototherapy.
We utilize Doara to carry the proinflammatory cytokine interleukin (IL)-12 and activate it to expose the IL-12 signal by irradiating NIR light near the tumor, thereby recruiting cytotoxic T cells that have cytotoxic effect to kill tumors.[3][4] Previously, toxicities was observed with systemic administration of this cytokine.[4][5] However, the therapy constructed with Doara can activate the IL-12 only near the tumor and display the IL-12 signal for a controllable short period, thereby minimizing the risk of excessive immune responses and controllably eliminating tumors.
Is that all?
1. Multiple wavelength photothermal switchers.
The specific wavelength that can excite the photothermal effect of AuNRs is referred to as the Surface Plasmon Resonance (SPR) peak, and the SPR peaks vary with different aspect ratios of gold nanorods.[6] This means that we can obtain a range of photothermal switches at different wavelengths by adjusting the aspect ratio of AuNRs.
This provides us with a broader range of options. For instance, we can utilize photothermal switches excited by different wavelength for selective drug release, sustained drug delivery, and the construction of programmable nanorobots and so on.
2. Programmammable regulation of protein activity.
Given Doara's remotely controllable characteristics and its applicability within the human body, we can envision the programmable regulation of important protein activities in vivo, such as signaling molecules or enzymes. For instance, we could load enzymes on Doara and control their activity through near-infrared light, thereby regulating metabolism in the human body.[7] Alternatively, we could load signaling molecules to modulate human signal transduction pathways.[8] Further, we even could load cyclins to regulate cell cycles. Thanks to Doara's remote controllability, we can activate Doara when needed to help us regulate our own physiological activities.
References
[1] Liu L, Wang X, Li Y, Liu J. Evaluation of probe-based ultra-sensitive detection of miRNA using a single-molecule fluorescence imaging method: miR-126 used as the model. Front Bioeng Biotechnol. 2023 Jan 24;11:1081488. doi: 10.3389/fbioe.2023.1081488. PMID: 36761298; PMCID: PMC9902880.
[2] Bentin T. A DNA nanocapsule with aptamer-controlled open-closure function for targeted delivery. Artif DNA PNA XNA. 2012 Jan-Mar;3(1):3-4. doi: 10.4161/adna.19843. PMID: 22679527; PMCID: PMC3368814.
[3] Um e Habiba, Mussarat Rafiq, Muhammad Babar Khawar, Bismillah Nazir, Gulfam Haider, Nadia Nazir The multifaceted role of IL-12 in cancer. Advances in Cancer Biology - Metastasis, Volume 5, 2022, 100053, ISSN 2667-3940, doi:10.1016/j.adcanc.2022.100053.
[4] Hughson AL, Hannon G, Salama NA, Vrooman TG, Stockwell CA, Mills BN, Garrett-Larsen J, Qiu H, Katerji R, Benoodt L, Johnston CJ, Murphy JD, Kruger E, Ye J, Gavras NW, Keeley DC, Qin SS, Lesch ML, Muhitch JB, Love TMT, Calvi LM, Lord EM, Luheshi N, Elyes J, Linehan DC, Gerber SA. Integrating IL-12 mRNA nanotechnology with SBRT eliminates T cell exhaustion in preclinical models of pancreatic cancer. Mol Ther Nucleic Acids. 2024 Sep 30;35(4):102350. doi: 10.1016/j.omtn.2024.102350. PMID: 39469666; PMCID: PMC11513558.
[5] Gollob JA, Mier JW, Veenstra K, McDermott DF, Clancy D, Clancy M, Atkins MB. Phase I trial of twice-weekly intravenous interleukin 12 in patients with metastatic renal cell cancer or malignant melanoma: ability to maintain IFN-gamma induction is associated with clinical response. Clin Cancer Res. 2000 May;6(5):1678-92. PMID: 10815886.
[6] Link S, El-Sayed MA. Optical properties and ultrafast dynamics of metallic nanocrystals. Annu Rev Phys Chem. 2003;54:331-66. doi: 10.1146/annurev.physchem.54.011002.103759. Epub 2002 Mar 21. PMID: 12626731.
[7] Samanta M, Saad N, Wu D, Crone NSA, Abramov-Harpaz K, Regev C, Cohen-Luria R, Boyle AL, Miller Y, Kros A, Ashkenasy G. A Photo-Switchable Peptide Fibril Esterase. Angew Chem Int Ed Engl. 2024 Sep 27:e202413810. doi: 10.1002/anie.202413810. Epub ahead of print. PMID: 39329502.
[8] Parisi C, Laneri F, Martins TJ, Fraix A, Sortino S. Nitric Oxide-Photodelivering Materials with Multiple Functionalities: From Rational Design to Therapeutic Applications. ACS Appl Mater Interfaces. 2024 Nov 6;16(44):59697-59720. doi: 10.1021/acsami.4c13478. Epub 2024 Oct 24. PMID: 39445390.
