Tumor immunotherapy based on immune checkpoint blockade (ICB) still suffers from low host response rate and non-specific distribution of immune checkpoint inhibitors, greatly compromising the therapeutic efficiency. Herein, cellular membrane stably expressing matrix metallopeptidase 2 (MMP2)-activated PD-L1 blockades is engineered to coat ultrasmall barium titanate (BTO) nanoparticle for overcoming the immunosuppressive microenvironment of tumors. The resulting M@BTO NPs can significantly promote the BTO's tumor accumulation, while the masking domains on membrane PD-L1 antibodies are cleaved when exposure to MMP2 highly expressed in tumor. With ultrasound (US) irradiation, M@BTO NPs can simultaneously generate reactive oxygen species (ROS) and O2 based on BTO mediated piezocatalysis and water splitting, significantly promoting the intratumoral infiltration of cytotoxic T lymphocytes (CTLs) and improving the PD-L1 blockade therapy to the tumor, resulting in effective tumor growth inhibition and lung metastasis suppression in a melanoma mouse model. This nanoplatform combines MMP2-activated genetic editing cell membrane with US responsive BTO for both immune stimulation and specific PD-L1 inhibition, providing a safe and robust strategy in enhancing immune response against tumor.

In the tumor microenvironment, macrophages predominately exhibit M2-type functionalities which promote malignant progression and cancer metastasis, thus posing a big hurdle for current anticancer strategies. Different approaches have been exploited to reverse the macrophages towards the M1 pro-inflammatory phenotype; however, it is hard to achieve tumor regression with this macrophage modulation alone. Herein we synthesized photothermal magnetic nanoclusters (MNCs) to test their capability for reprograming M2 macrophages towards the M1 phenotype. We demonstrated that these photothermal MNCs themselves can effectively trigger this desired macrophage repolarization, increase the phagocytosis of macrophages at the tumor site, and cause subsequent T cell activation with enhanced systemic cytokine release, leading to cancer cell killing both in vitro and in vivo. More interestingly, it was found that the photothermal effect can further facilitate this immune activation to a greater extent, inducing much higher level of macrophage repolarization and T cell infiltration into the tumor site as well as eliciting a much more efficient antitumor effect compared with MNCs alone. Our findings demonstrate that MNCs combined with their photothermal effect can reverse the local suppressive environment of the tumor by macrophage and T cell modulation, providing an effective approach to trigger systemic immune responses that contribute to an enhanced overall anticancer outcome and the suppression of cancer metastasis.

Ultrasound is widely used in biomedical engineering and has applications in conventional diagnosis and drug delivery. Recent advances in ultrasound-induced drug delivery have been summarized previously in several reviews that have primarily focused on the fabrication of drug delivery carriers. This review discusses the mechanisms underlying ultrasound-induced drug delivery and factors affecting delivery efficiency, including the characteristics of drug delivery carriers and ultrasound parameters. Firstly, biophysical effects induced by ultrasound, namely thermal effects, cavitation effects, and acoustic radiation forces, are illustrated. Secondly, the use of these biophysical effects to enhance drug delivery by affecting drug carriers and corresponding tissues is clarified in detail. Thirdly, recent advances in ultrasound-triggered drug delivery are detailed. Safety issues and optimization strategies to improve therapeutic outcomes and reduce side effects are summarized. Finally, current progress and future directions are discussed.

Ultrasound has been broadly used in biomedicine for both tumor diagnosis as well as therapy. The applications of recent developments in micro/nanotechnology promote the development of ultrasound-based biomedicine, especially in the field of ultrasound-based drug delivery and tumor therapy. Ultrasound can activate nano-sized drug delivery systems by different mechanisms for ultrasound- triggered on-demand drug release targeted only at the tumor sites. Ultrasound Targeted Microbubble Destruction (UTMD) technology can not only increase the permeability of vasculature and cell membrane via sonoporation effect but also achieve in situ conversion of microbubbles into nanoparticles to promote cellular uptake and therapeutic efficacy. Furthermore, High Intensity Focused Ultrasound (HIFU), or Sonodynamic Therapy (SDT), is considered to be one of the most promising and representative non-invasive treatment for cancer. However, their application in the treatment process is still limited due to their critical treatment efficiency issues. Fortunately, recently developed micro/nanotechnology offer an opportunity to solve these problems, thus improving the therapeutic effect of cancer. This review summarizes and discusses the recent developments in the design of micro- and nano- materials for ultrasound-based biomedicine applications.

Hypoxia in a solid tumor microenvironment (TME) can lead to the overexpression of hypoxia-inducible factor-1α (HIF-1α), which correlates to tumor metastasis. Reactive oxygen species (ROS) induced tumor cell apoptosis is becoming a promising method in tumor treatment. Currently, the ROS generating systems, e.g., photodynamic treatment and sonodynamic treatment, highly depend on oxygen (O2) in the tumor microenvironment (TME). However, the level of O2 in TME is too low to produce enough ROS. Herein, we developed an ultrasmall DSPE-PEG2000 coated barium titanate nanoparticle (P-BTO) for tumor treatment based on ultrasound triggered piezocatalysis and water splitting. Interestingly, irradiated by ultrasound, the surface of ultasmall P-BTO nanoparticles produced imbalance charges, which induced a cascade of redox reaction processes to simultaneously generate ROS and O2, the latter one was hardly generated in large-sized barium titanate nanoparticles. The as-synthesized P-BTO reached the highest accumulation in the tumor site at 4 h after intravenous injection. The results showed that the produced O2 significantly alleviated the hypoxia of TME to down-regulate the expression of HIF-1α, and the produced ROS can efficiently kill tumor cells. Moreover, the tumor metastasis was also inhibited, providing a different way to treat triple-negative breast cancer, which was easily metastatic and lacked effective treatments in the clinic.

>A chronic autoimmune disease named rheumatoid arthritis(RA) is characterized mainly by synovitis, which has high morbidity, disability and mortality rates. In addition, the aetiology and pathogenesis of RA have not been fully determined. RA is usually accompanied by persistent arthritic pain, swelling, stiffness, and functional disorders; in severe cases, it may result in cardiovascular, pulmonary, psychological and skeletal diseases(Scott et al.,2010).

The center dot OH induced apoptosis is a promising strategy for tumor treatment. Many current center dot OH generating systems are highly dependent on H2O2 in tumor microenvimnment (TME). However, the H2O2 level in the TME is not high enough to produce sufficient center dot OH. Herein, we develop a biomimetic nano-catalyst based on TiO2/Fe3O4 platform (designed as "FTP") to initiate a cascade of biochemical reactions to produce center dot OH in TME. In this platform, the modified TiO2 acting as H2O2 adsorber can promote the concentration of H2O2 around and significantly amplify Fenton reaction efficiency of Fe3O4 to induce more cell apoptosis through center dot OH mediated mechanism, thereby resulting in remarkable inhibition of tumor growth. The as-synthesized FTP, with diameter of 7.20 +/- 1.80 nm, could efficiently accumulate in tumor via the enhanced permeability and retention (EPR) effect and act as negative T2-weighted MRI contrast agent. The results showed that the FTP could induce a significantly higher cytotoxicity profile than naked Fe3O4 nanoparticles. More specifically, the FTP exhibited significant therapeutic performance of tumors than naked Fe3O4, TiO2, and control groups.

As an alternative to photodynamic therapy (PDT), ultrasound-triggered tumor sonodynamic therapy (SDT) has garnered significant attention, owing to its high tissue penetration, few side effects, and reliable patient compliance. A sonosensitizer is the most important component in SDT, and high-quantum-yield safe sonosensitizers are crucial for SDT. Existing sonosensitizers mainly include organic sonosensitizers and inorganic sonosensitizers. Organic sonosensitizers, mainly some small dye molecules, have been widely studied. However, organic sonosensitizers have limited utility owing to their poor stability, rapid blood clearance, and potential phototoxicity. In contrast, inorganic sonosensitizers have stable chemical properties, long circulation time in the blood and can effectively reduce phototoxicity. In addition to their utilization as sonosensitizers, some inorganic nanoparticles can also operate as carriers for delivering organic sonosensitizers, effectively overcoming the inherent shortcomings of organic small-molecule sonosensitizers. This review mainly focuses on inorganic nanomaterial-based SDT, the possible mechanisms of SDT, and newly developed inorganic sonosensitizers, as well as the challenges and possible solutions associated with their clinical translation are introduced.

Photothermal therapy (PTT) is a promising tumor therapy strategy; however, heterogeneous heat distribution over the tumor often exists, resulting in insufficient photothermal ablation and potential risk of cancer metastasis, which has been demonstrated to be associate with platelets. Herein, a near-infrared (NIR) photothermal agent of IR780 was conjugated with MRI agent of Gd-DOTA via a disulfide linkage (ICD-Gd), which was coassembly with lipid connecting tumor-homing pentapeptide CREKA (Cys-Arg-Glu-Lys-Ala) (DSPE-PEG-CREKA) to encapsulate a platelet inhibitor of ticagrelor (Tic), affording a multistimuli-responsive nanosystem (DPC@ICD-Gd-Tic). The nanosystem with completely quenching fluorescence could specifically target the tumor-associated platelets and showed pH/reduction/NIR light-responsive drug release, which simultaneously resulting in dis-assembly of nanoparticle and fluorescence recovery, enabling the drug delivery visualization in tumor in situ via activatable NIR fluorescence/MR bimodal imaging. Finally, DPC@ICD-Gd-Tic further integrated the photoinduced hyperthermia and platelet function inhibitor to achieve synergistic anticancer therapy, leading to ablation of primary tumor cells and effectively suppressed their distant metastasis. The number of lung metastases in 4T1 tumor bearing mice was reduced by about 90%, and the size of tumor was reduced by about 70%, while half of the mouse was completely cured by this smart nanosystem.

With high level of morbidity and mortality, tumor is one of the deadliest diseases worldwide. Aiming to tackle tumor, researchers have developed a lot of strategies. Among these strategies, the minimally invasive therapy (MIT) is very promising, for its capability of targeting tumor cells and resulting in a small incision or no incisions. In this review, we will first illustrate some mechanisms and characteristics of tumor metastasis from the primary tumor to the secondary tumor foci. Then, we will briefly introduce the history, characteristics, and advantages of some of the MITs. Finally, emphasis will be, respectively, focused on an overview of the state-of-the-art of the HIFU-, PDT-, PTT-and SDT-based anti-tumor strategies on each stage of tumor metastasis.

Hypoxia, as a typical factor in a tumor microenvironment, plays a vital role in tumor treatment resistance, tumor invasion and migration. Hypoxia inducible factor (HIF), as the vital response element of hypoxia, mediates these untoward effects through a series of downstream reactions. Cancer treatments such as photodynamic therapy (PDT), radiotherapy (RT) and chemotherapy are severely hindered by hypoxia and HIF, back, however, could be intelligently manipulated through nanocomposite materials for their great potentiality to combine different functions. Herein, we reviewed the smart strategies in emerging research studies to overcome hypoxia toward the enhancement of tumor therapy.

Thermosensitive liposomes have demonstrated great potential for tumor-specific chemotherapy. Near infrared (NIR) dyes loaded liposomes have also shown improved photothermal effect in cancer theranostics. However, the instability of liposomes often causes premature release of drugs or dyes, impeding their antitumor efficacy. Herein, we fabricated a highly stable thermo-responsive bubble-generating liposomal nanohybrid cerasome with a silicate framework, combined with a NIR dye to achieve NIR light stimulated, tumor-specific, chemo-photothermal synergistic therapy. Methods: In this system, NIR dye of 1,1'-Dioctadecyl-3,3,3',3'- Tetramethylindotricarbocyanine iodide (DiR) with long carbon chains was self-assembled with a cerasome-forming lipid (CFL) to encapsulate ammonium bicarbonate (ABC), which was further used for actively loading doxorubicin (DOX), affording a thermosensitive and photosensitive DOX-DiR@cerasome (ABC). Results: The resulting cerasome could disperse well in different media. Upon NIR light mediated thermal effect, ABC was decomposed to generate CO2 bubbles, resulting in a permeable channel in the cerasome bilayer that significantly enhanced DOX release. After intravenous injection into tumor-bearing mice, DOX-DiR@cerasome (ABC) could be efficiently accumulated at the tumor tissue, as monitored by DiR fluorescence, lasting for more than 5 days. NIR light irradiation was then performed at 36h to locally heat the tumors, resulting in immediate CO2 bubble generation, which could be clearly detected by ultrasound imaging, facilitating the monitoring process of controlled release of the drug. Significant antitumor efficacy could be obtained for the DOX-DiR@cerasome (ABC) + laser group, which was further confirmed by tumor tissue histological analysis.