Phototherapy has emerged as a novel therapeutic modality for cancer treatment, but its low therapeutic efficacy severely hinders further extensive clinical translation and application. This study reports amplifying the phototherapeutic efficacy by constructing a near‐infrared (NIR)‐responsive multifunctional nanoplatform for synergistic cancer phototherapy by a single NIR irradiation, which can concurrently achieve mitochondria‐targeting phototherapy, synergistic photothermal therapy (PTT)/photodynamic therapy (PDT), self‐sufficient oxygen‐augmented PDT, and multiple‐imaging guidance/monitoring. Perfluorooctyl bromide based nanoliposomes are constructed for oxygen delivery into tumors, performing the functions of red blood cells (RBCs) for oxygen delivery (“Nano‐RBC” nanosystem), which can alleviate the tumor hypoxia and enhance the PDT efficacy. The mitochondria‐targeting performance for enhanced and synergistic PDT/PTT is demonstrated as assisted by nanoliposomes. In particular, these “Nano‐RBCs” can also act as the contrast agents for concurrent computed tomography, photoacoustic, and fluorescence multiple imaging, providing the potential imaging capability for phototherapeutic guidance and monitoring. This provides a novel strategy to achieve high therapeutic efficacy of phototherapy by the rational design of multifunctional nanoplatforms with the unique performances of mitochondria targeting, synergistic PDT/PTT by a single NIR irradiation (808 nm), self‐sufficient oxygen‐augmented PDT, and multiple‐imaging guidance/monitoring.

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High-intensity focused ultrasound (HIFU) is deemed to be a promising noninvasive therapeutic modality for cancers as well as non-neoplastic diseases. However, the accuracy of the technique in the diagnosis and treatment of tumors remains unsatisfactory. HIFU, when combined with multifunctional synergistic agents (SAs), has the potential to be of greater diagnostic and therapeutic efficacy. Here we describe a smart and multifunctional hollow mesoporous Prussian blue (HMPBs) theranostic nanoplatform, the hollow structure of which is capable of encapsulating doxorubicin (DOX) and perfluorohexane (HMPBs-DOX/PFH). In vitro and in vivo studies validated that HMPBs-DOX/PFH can be used as an amplifiable dual-mode imaging contrast agent, which can simultaneously enhance ultrasound (US) and photoacoustic (PA) imaging for guiding and monitoring tumor therapy. When exposed to HIFU, this versatile HMPBs-DOX/PFH agent could increase the cavitation effect and use lower HIFU intensity to achieve coagulative necrosis. Furthermore, it significantly accelerated the release of DOX thereby enhancing chemotherapeutic efficacy and avoiding systemic side effects of the drug. Such a novel theranostic nanoplatform is expected to integrate dual-mode guided imaging with greater therapeutic efficacy and fewer side effects and is very promising for the noninvasive synergistic tumor therapy.

Thrombotic disease is extremely harmful to human health, and early detection and treatment can improve the prognosis and reduce mortality. Multimodal molecular imaging can provide abundant information about thrombi, but to date, few studies have used multimodal and multifunctional nanoparticles (NPs) for thrombus detection and for targeting thrombolysis. In this study, phase transition multimodal and multifunctional NPs (EWVDV-Fe-Ink-PFH NPs) were constructed for the first time using a three-step emulsification and carbodiimide method, and the physical and chemical properties of the NPs were investigated. The targeting abilities of the NPs and multimodal imaging, that is, photoacoustic, magnetic resonance, and ultrasound imaging, were successfully achieved in vitro and in vivo. The ability of the EWVDV peptide on the NPs to effectively target the P-selectin of thrombi was confirmed by multimodal imaging and pathology, and the penetration depths of the NPs into the thrombi were far deeper than the previously reported depths. Moreover, a perfluorohexane (PFH) phase transition induced by low-intensity focused ultrasound irradiation enabled the EWVDV-Fe-Ink-PFH NPs to cause thrombolysis in vitro. In summary, EWVDV-Fe-Ink-PFH NPs are a theranostic contrast agent that will provide a simple, effective, and noninvasive approach for the diagnosis and treatment of thrombosis.

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Multifunctional nanoparticles have been reported for cancer detection and treatment currently. However, the accurate diagnosis and efficient treatment for tumors are still not satisfied. Here we report on the development of targeted phase change multimodal polymeric nanoparticles for the imaging and treatment of HER2-positive breast cancer.Methods: We evaluated the multimodal imaging capabilities of the prepared nanoparticles in vitro using agar-based phantoms. The targeting performance and cytotoxicity of the nanoparticles were examined in cell culture using SKBR3 (over-expressing HER2) and MDA-MB-231 (HER2 negative) cells. We then tested the magnetic resonance (MR)/ photoacoustic (PA)/ ultrasound (US)/ near-infrared fluorescence (NIRF) multimodal imaging properties and photothermal effect of the nanoparticles in vivo using a SKBR3 breast xenograft model in nude mice. Tissue histopathology and immunofluorescence were also conducted.Results: Both in vitro and in vivo systematical studies validated that the hybrid nanoparticles can be used as a superb MR/US/PA/NIRF contrast agent to simultaneously diagnose and guide tumor photothermal therapy (PTT). When irradiated by a near infrared laser, the liquid PFP vaporizes to a gas, rapidly expelling the contents and damaging surrounding tissues. The resulting micro-sized bubbles provide treatment validation through ultrasound imaging. Localization of DIR and SPIO in the tumor region facilitate photothermal therapy for targeted tumor destruction. The mice treated with HER2 targeted nanoparticles had a nearly complete response to treatment, while the controls showed continued tumor growth.Conclusion: This novel theranostic agent may provide better diagnostic imaging and therapeutic potential than current methods for treating HER2-positive breast cancer.

Background: The construction of theranostic nanosystems with concurrently high biosafety and therapeutic performance is a challenge but has great significance for the clinical translation of nanomedicine for combating cancer.Methods: Bio-inspired melanin-based nanoliposomes (Lip-Mel) as theranostic agents were constructed for simultaneous photoacoustic (PA) imaging- and T1-weighted magnetic resonance (MR) imaging-guided photothermal ablation of tumors, which was demonstrated both in vitro and in vivo. The high biosafety of Lip-Mel was also systematically evaluated.Results: The achieved Lip-Mel nanoliposomes demonstrated their imaging capability for both PA and T1-weighted MR imaging (r1 = 0.25 mM-1·s-1) both in vitro and in vivo, providing the potential for therapeutic guidance and monitoring. Importantly, the desirable photothermal-conversion efficiency of the as-prepared Lip-Mel achieved complete eradication of tumors in breast cancer-bearing mice, exhibiting remarkable photothermal-based therapeutic performance. In particular, the efficient encapsulation of melanin into the PEGylated liposome mitigated the potential toxicity of melanin and improved the photothermal performance of the loaded melanin. Systematic in vivo biosafety evaluations demonstrated the high biocompatibility of Lip-Mel at a high dose of 100 mg/kg.Conclusion: In this work, we reported a bioinspired strategy where melanin, a natural product in the human body, is encapsulated into PEGylated nanoliposomes for efficient theranostics with high biocompatibility. This work provides a new strategy for creating desirable theranostic agents with concurrent high biocompatibility and satisfactory theranostic performance through the use of materials that totally originate from biosystems.

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