sonosensitizer for breast cancer treatment. significantly increased reactive oxygen species generation was observed in breast cancer cells treated with folic acid-conjugated exosomes. this is one example of a sonosensitizer used to treat a specific cancer using sonodynamic therapy. another example of exosome-based sonodynamic therapy was illustrated by liu et al. in this study, exosomes were decorated with porphyrin sensitizers and this system was used with an external ultrasound device to control and target drug delivery through sdt. liu et al. provided a non-invasive method for treating cancer through extracorporeal activation of exosomes through ultrasound. microbubbles mechanisms for loading microbubbles with drug due to their ability to oscillate with exposure to low-frequency ultrasound, microbubbles have been used as contrast agents in order to visualize tissues in which the microbubbles have permeated. however, when these microspheres are exposed to higher pressure ultrasound, they can rupture, which could be beneficial for drug delivery purposes. through sdt, these microbubbles could be selectively bursted at the tumor microenvironment in order to decrease systemic levels of the encapsulated drug and increase therapeutic efficacy. when applying sdt, the increase in acoustic pressure leads to the inertial cavitation, or collapse of the microbubble and local release of the cargo within. the inertial cavitation of the microbubbles when exposed to sdt is also referred to as ultrasound mediated microbubble destruction (ummd). the shell of microbubbles can be decorated with different components, including polymers, lipids, or proteins depending on their intended purpose. microbubbles have also been used for the localized release of attached cargo. this cargo is typically chemotherapeutics, antibiotics, or genes. different drugs can be directly loaded into the microbubble with methods such as conjugation and nanoparticle, liposome loading, and genes. the combination of genes and sdt is referred to as sonotransfection. examples of outer shell modifications can be seen in a study by mcewan et al. which found that lipid microbubbles showed reduced stability when sonosensitizers were added to their shells. however, attaching the polymer poly lactic-co-glycolic acid (plga) to the shell resulted in increased stability compared to the lipid microbubbles without losing other desirable properties such as targeted delivery and selective cytotoxicity. in another study, mcewan et al. investigated the ability of microbubbles carrying oxygen to increase production of reactive oxygen species, which are a necessary component of sdt, in the hypoxic environment of many solid tumors. these microbubbles were stabilized with lipids and a rose bengal sonosensitizer was attached to the surface to treat pancreatic cancer. their work showed that coupling oxygen-loaded microbubbles that are sensitive to ultrasound with sonosensitizing drugs could allow for increased drug activation at the desired target even if hypoxia is present. examples of therapeutics that have been loaded into microbubbles are gemcitabine, paclitaxel nanoparticles, plasmid dna and 2,2′-azobisdihydrochloride loaded liposomes. due to the targeting nature of the ligands connected to the microbubble, it allows for the controlled and specific targeting of the desired tissue for treatment. another study performed by nesbitt et al. has shown improved tumor reduction when gemcitabine was loaded into the microbubble and applied to a human pancreatic cancer xenograft model with sdt. nanobubbles similar to microbubbles, nanobubbles have shown efficacy in sdt. however, due to their smaller size, nanobubbles are able to reach targets that microbubbles cannot. nanobubbles can reach deeper tissue and travel past the vasculature. previous research has demonstrated that nanobubbles are more capable of reaching the tumor since they can permeate endothelial cells and migrate away from the vasculature. one study by nittayacharn et al. developed doxorubicin-loaded nanobubbles and paired them with porphyrin sensitizers to be used in sdt for treatment of breast and ovarian cancer cells in vitro. they found an almost 70% increase in cytotoxicity when using sdt compared to only perfluoropropane nanobubbles filled with iridium(iii). additionally, compared to empty nanobubbles and/or free iridium(iii), they observed greatest reactive oxygen species generation in the iridium(iii)-nanobubbles exposed to ultrasound. these results demonstrate that nanobubbles loaded with a sonosensitizer and exposed to ultrasound could be a potential effective treatment for cancer using sdt. as with microbubbles, nanobubbles have also shown promise as oxygen-delivering vesicles to enhance the effectiveness of sdt. in order to mitigate hypoxia of target tissue, owen et al. used a pancreatic cancer rodent model to deliver phospholipid stabilized nanobubbles filled with oxygen. the mice were divided into groups, one that received oxygen-filled nanobubbles prior to injection of a sonosensitizer and one that didn't. a statistically significant difference between the levels of oxygen in the tumors of the two groups was observed, indicating that nanobubbles could be an effective addition to sdt to treat cancers in a hypoxic environment. applications combination with other therapies sonodynamic therapy can be combined with other therapeutic techniques to enhance treatment efficacy for various types of cancers and diseases. sdt can be combined with photodynamic therapy, chemotherapy, radiation, mri, and immunotherapy. pdt has often been used in combination with sdt as sonosensitizers are also photosensitive. during initial development of sdt, umemura et al., have determined that hematoporphyrins were able to initiate cell death similarly to pdt. this is due to sdt being able to initiate sonoluminescence. however, the advantage of sdt over pdt is that it can penetrate deep and precisely into the targeted tissue. in a study by lui et al., it was shown that using a combination of these two delivery methods results in increased cytotoxicity with sino porphyrin in a metastatic xenograft model. in another example of combining sdt with pdt, borah et al. investigated the advantage of 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (hhph), a photodynamic therapy drug, as a sonosensitizer and a photosensitizer for treating glioblastoma. combining these therapies showed increased cell kill/tumor response, possibly caused by synergistic effects. the goal of a study by browning et al. was to investigate the potential enhancement of chemoradiation efficacy through combining it with sonodynamic therapy in pancreatic cancer patients. in one model, survival increased with the combination compared to chemoradiation alone. differences in the results for the two different models could be attributed to variations in tumor organization. the tumors that showed the greatest reduction in size were less vascularized, perhaps making them more vulnerable to sdt. another study, by huang et al. used elements of mesoporous organosilica-based nanosystems to fabricate a sonosensitizer to be used with mri-guided sdt. increased cell death and inhibiting tumor growth was induced by the sonosensitizers, indicating high sdt efficiency. this shows how sdt can assist with both removal and inhibition of tumor growth. sdt has also been combined with immunotherapy. a study by lin et al. aimed to use cascade immuno-sonodynamic therapy to enhance tumor treatment using antibodies. the nanosonosensitizers resulted in high drug loading efficiency and a tumor-specific adaptive immune response. this serves as an example as to how sdt can be coupled with checkpoint blockade immunotherapy to enhance efficiency in cancer treatments. another study by yue et al. strived to combine checkpoint-blockade immunotherapy with nanosonosensitizers-augmented noninvasive sonodynamic therapy. along with inhibiting lung metastasis, this combination promoted an anti-tumor response that prohibited tumor growth. this provides a proof-of-concept for combining sdt with another therapy to enhance treatment effects for the short and long term. cancer treatment the treatment of many different types of cancers has been investigated using sonodynamic therapy both in vitro and/or in vivo including, glioblastoma, pancreatic, breast, ovarian, lung, prostate, liver, stomach, and colon cancers. a study by gao et al. showed that sdt is capable of inhibiting angiogenesis through the production of ros. this hindered the proliferation, migration, and invasion of endothelial cells, tumor growth, intratumoral vascularity, and vascular endothelial growth factor expression within the tumor cell in xenograft rat models. hachimine et al. performed a large in vitro study testing sdt on seventeen different cancer cell lines. the types of cancers included were pancreatic, breast, lung, prostate, liver, stomach, and colon cancers. the most successful treatment was that of lung cancer with 23.4% cell viability post-therapy. qu et al. aimed to develop an “all-in-one” nanosensitizer platform triggered by sdt that combines various diagnostic and therapeutic effects to treat glioblastoma. apoptosis was successfully induced and mitophagy was inhibited in glioma cells. this is an example of how sdt can be used with a different platform to treat glioblastoma. borah et al., as mentioned above, also investigated the ability of sdt (and pdt) to treat glioblastoma and found that sdt (combined with pdt) was able to increase the number of tumor cells killed. mcewan et al. and owen et al. both demonstrated the use of micro/nanobubbles to enhance the oxygen concentration near hypoxic pancreatic tumors, thereby increasing the efficacy of sdt. breast cancer morphologic and immunohistochemical features of triple negative breast cancer 12% of women in the us will be diagnosed with breast cancer. metastasis and recurrence is a large challenge for deep-seated solid state tumors. sdt is currently being explored as a treatment method for breast cancer, while avoiding the side effects associated with current therapeutic methods. there has been shown success in utilizing sdt in animal and human clinical trials in reduction of tumor size through mitochondrial targeting to initiate apoptosis of tumor cells and autophagy and immune response regulation. however, there are still complications with proper therapeutic efficacy when used alone. glioma glioblastoma malignant glioma is an extremely difficult to treat brain tumor that is a leading cause of death worldwide and half of cancer-related deaths. complications associated with treating glioma include the blood brain barrier (bbb). this protective mechanism for the brain also raises challenges for drug delivery through the tight junctions between endothelial cells, only allowing small lipid-soluble drugs (<400 da) to permeate. current delivery methods are surgery and chemotherapy. sdt has been implemented as a method to open the bbb and has shown success in opening tight junctions for delivery. examples of sonosensitizers that have shown success in glioma treatment are hematopor-phyrin monomethyl ether (hmme), porfimer sodium (photofrin), di-sulfo-di-phthalimidomethyl phthalolcyaninezinc (znpcs2p2), photolon, 5-aminolevulinic acid (5-ala), and rose bengal (rb). these have shown to induce effects such as opening of the bbb, improved vascular permeability, and apoptosis of glioma cells. prostate cancer benign prostatic hyperplasia prostate cancer is the second cause of cancer and the most common malignancy associated with deaths in men worldwide. current methods of treatments are invasive resection therapy, radiation therapy, and prostatectomy that can cause complications such as incontinence, impotence, and damage to surrounding organs and tissues. current studies have shown success in using sdt as a stand-alone treatment. sdt uses mitochondria related apoptosis for the reduction of cell viability. sdt for prostate cancer treatment has also been used alongside chemotherapeutics such as docetaxel microbubbles. this has shown to enhance the effects of docetaxel through a reduction in tumor perfusion and enhanced necrosis and apoptosis. the sdt and docetaxel group showed reduction in tumor growth. overall, the use of sdt has shown promising results in prostate cancer treatment. arterial diseases sonodynamic therapy could be used to treat more than just cancers. atherosclerosis, which is a chronic arterial disease, is another target that has been observed in the literature. this disease occurs when fatty plaques aggregate on the inner surface of the artery and could be caused by malfunctions in lipid metabolism. more specifically, atherosclerosis is caused by an increase in endothelial permeability causing low-density lipoprotein particles to become oxidized and undergo sedimentation. these lipoproteins cause an increase in macrophages and lead to intensified plaque build up. as a result, the high influx of macrophages is the target for as treatment in order to slow plaque build-up. alongside the relationship between plaque build-up and macrophages, monocyte's differentiation into macrophages exacerbates the aforementioned process in addition to causing inflammation. normal artery versus atherosclerosis a study by wang et al. aimed to understand the underlying mechanisms regarding the potential effect of non-lethal sdt on atheroscleroic plaques. it was determined that non-lethal sdt prevents plaque development. a study performed by jiang et al., showed success in sdt through the reduction of macrophage inflammatory factors such as tnf-alpha, il-12, and il-1b. they also showed that sdt could inhibit plaque inflammation in patients with peripheral artery disease and continue to promote positive results for longer than six months. popular sonosensitizers for as treatment are protoporphyrin ix (ppix) and 5-aminolevulinic acid (5-ala). ppix is often used in pdt and is generated through 5-ala, a non ultrasound-activated component, through increasing ppix concentration within a cell. a