Ultrasound-Mediated Remotely Controlled Nanovaccine Delivery for Tumor Vaccination and Individualized Cancer Immunotherapy.

Vaccines are one of utmost important weapons in modern medicine to fight a wide range of diseases. To achieve optimal vaccination effects, repeated injections of vaccines are often required, which would largely decrease patient comfort. Herein, an ultrasound-responsive self-healing hydrogel system loaded with nanovaccines is designed for remotely controlled tumor vaccine release and individualized cancer immunotherapy. The gel could be transformed into sol status in response to ultrasound treatment, allowing a burst release of nanovaccines, and self-healed to gel afterward. For mice with a single subcutaneous injection of nanovaccine-loaded gel and multiple ultrasound treatments, repeatedly released nanovaccines could elicit antitumor immune responses, which in combination with immune checkpoint blockade could effectively inhibit established tumors, and prevent postoperative tumor metastases and recurrence based on our personalized nanovaccine system. This work presents an easy-to-operate strategy to realize controllable and durable delivery of vaccines against cancer and potentially other types of diseases.

Thermo-Triggered In Situ Chitosan-Based Gelation System for Repeated and Enhanced Sonodynamic Therapy Post a Single Injection.

Sonodynamic therapy (SDT) by utilizing ultrasonic waves triggers the generation of reactive oxygen species (ROS) with the help of sonosensitizers to destruct deep-seated tumors has attracted great attention. However, the efficacy of SDT may not be robust enough due to the insufficient oxygen supply within solid tumors. Additionally, repeated injections and treatments, which are often required to achieve the optimal therapeutic responses, may cause additional side effects and patient incompliance. Herein, a thermo-triggered in situ hydrogel system is developed in which catalase (CAT) conjugated with sonosensitizer meso-tetra (4-carboxyphenyl) porphine (TCPP) is mixed into chitosan (CS) and beta-glycerol phosphate disodium (GP) to form the precursor solution. After injection of the precursor solution into tumors, the in situ sol-gel transformation will occur as triggered by the body temperature, resulting in the localized tumor retention of TCPP-CAT. The locally restrained TCPP-CAT not only produces ROS under ultrasonic treatment, but also sustainably reverses the oxygen-deficient status in solid tumors by triggering the O2 generation from the decomposition of endogenous H2 O2 , further promoting the efficacy of SDT. As a result, the repeated SDT after a single dose injection of such a hydrogel can offer robust treatment effects to effectively eradicate tumors.

Near-Infrared Light-Responsive Nitric Oxide Delivery Platform for Enhanced Radioimmunotherapy.

Radiotherapy (RT) is a widely used way for cancer treatment. However, the efficiency of RT may come with various challenges such as low specificity, limitation by resistance, high dose and so on. Nitric oxide (NO) is known a very effective radiosensitizer of hypoxic tumor. However, NO cannot circulate in body with high concentration. Herein, an NIR light-responsive NO delivery system is developed for controlled and precisely release of NO to hypoxic tumors during radiotherapy. Tert-Butyl nitrite, which is an efficient NO source, is coupled to Ag2S quantum dots (QDs). NO could be generated and released from the Ag2S QDs effectively under the NIR irradiation due to the thermal effect. In addition, Ag is also a type of heavy metal that can benefit the RT therapy. We demonstrate that Ag2S NO delivery platforms remarkably maximize radiotherapy effects to inhibit tumor growth in CT26 tumor model. Furthermore, immunosuppressive tumor microenvironment is improved by our NO delivery system, significantly enhancing the anti-PD-L1 immune checkpoint blockade therapy. 100% survival rate is achieved by the radio-immune combined therapy strategy based on the Ag2S NO delivery platforms. Our results suggest the promise of Ag2S NO delivery platforms for multifunctional cancer radioimmunotherapy.

Ultrasound-Responsive Conversion of Microbubbles to Nanoparticles to Enable Background-Free in Vivo Photoacoustic Imaging.

Photoacoustic (PA) imaging based on the photon-to-ultrasound conversion allows the imaging of optical absorbers in deep tissues with high spatial resolution. However, the inherent optical absorbance of biomolecules (e.g., hemoglobin, melanin, etc.) would show up as tissue background signals to interfere with signals from the contrast agent during in vivo PA imaging, limiting the imaging sensitivity. Herein, an ultrasound (US)-responsive PA imaging probe based on microbubbles (MBs) containing gold nanoparticles (Au NPs) is designed for in vivo "background-free" PA imaging. The obtained Au@lip MBs with separated Au NPs decorated within the lipid shell of MBs show low PA signals under near-infrared (NIR) excitation. Interestingly, under exposure to US pulses, those Au@lip MBs would burst to form nanoscale aggregates of Au@lip NPs, which exhibit significantly enhanced NIR PA signals due to their red-shifted surface plasmon resonance. Therefore, by subtracting the PA image captured pre-US burst from that captured post-US burst, the tissue background PA signals could be deducted to enable background-free PA imaging with high sensitivities as demonstrated by multiple ex vivo and in vivo experiments. This work presents a simple yet effective strategy to deduct background signals during PA imaging, which is promising for accurate PA detection of targets in tissues with a strong background.

Light-Triggered In Situ Gelation to Enable Robust Photodynamic-Immunotherapy by Repeated Stimulations.

Photodynamic therapy (PDT) has shown the potential of triggering systemic antitumor immune responses. However, while the oxygen-deficient hypoxic tumor microenvironment is a factor that limits the PDT efficacy, the immune responses after conventional PDT usually are not strong enough to eliminate metastatic tumors. Herein, a light-triggered in situ gelation system containing photosensitizer-modified catalase together with poly(ethylene glycol) double acrylate (PEGDA) as the polymeric matrix is designed. Immune adjuvant nanoparticles are further introduced into this system to trigger robust antitumor immune responses after PDT. Following local injection of the mixed precursor solution into tumors and the subsequent light exposure, polymerization of PEGDA can be initiated to induce in situ gelation. Such hybrid hydrogel with long-term tumor retention of various agents and the ability to enable persistent tumor hypoxia relief can enable multiple rounds of PDT, which results in significantly enhanced immune responses by multiround stimulation. Further combination of such gel-based multiround PDT with anticytotoxic T-lymphocyte antigen-4 checkpoint blockade offers not only the abscopal effect to inhibit growth of distant tumors but also effective long-term immune memory protection from rechallenged tumors. Therefore, such a light-triggered in situ gelation system by a single-dose injection can enable greatly enhanced photoimmunotherapy by means of repeated stimulations.