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5-Aminolevulinic acid-based photodynamic therapy heavily depends on the biological transformation efficiency of 5-aminolevulinic acid to protoporphyrin IX, while the lack of an effective delivery system and imaging navigation are major hurdles in improving the accumulation of protoporphyrin IX and optimizing therapeutic parameters. Herein, we leverage a synthetic biology approach to construct a transdermal theranostic microneedle patch integrated with 5-aminolevulinic acid and catalase co-loaded tumor acidity-responsive copper-doped calcium phosphate nanoparticles for efficient 5-aminolevulinic acid-based photodynamic therapy by maximizing the enrichment of intratumoral protoporphyrin IX. We show that continuous oxygen generation by catalase in vivo reverses tumor hypoxia, enhances protoporphyrin IX accumulation by blocking protoporphyrin IX efflux (downregulating hypoxia-inducible factor-1α and ferrochelatase) and upregulates protoporphyrin IX biosynthesis (providing exogenous 5-aminolevulinic acid and upregulating ALA-synthetase). In vivo fluorescence/photoacoustic duplex imaging can monitor intratumoral oxygen saturation and protoporphyrin IX metabolic kinetics simultaneously. This approach thus facilitates the optimization of therapeutic parameters for different cancers to realize Ca2+/Cu2+-interferences-enhanced repeatable photodynamic therapy, making this theranostic patch promising for clinical practice. An effective delivery system and imaging method for 5-Aminolevulinic acid (5-ALA)-based photodynamic therapy facilitated by the conversion of 5-ALA to protoporphyrin IX (PpIX) are lacking. Here, reversing the hypoxic tumour microenvironment can increase the in vivo biosynthesis of PpIX through the regulation of PpIX-related synthetases for traceable photodynamic therapy. [ABSTRACT FROM AUTHOR]

Background: Sonodynamic therapy (SDT) has emerged as a noninvasive therapeutic modality that involves sonosensitizers and low-intensity ultrasound. However, owing to the rapid recombination of charge carriers, most of the sonosensitizers triggered poor reactive oxygen species (ROS) generation, resulting in unsatisfactory sonodynamic therapeutic effects. Results: Herein, a photo/sono-responsive nanoplatform was developed through the in-situ systhesis of TiO2-x on the surface of two-dimensional MXene (titanium carbide, Ti3C2) for photoacoustic/photothermal bimodal imaging-guided near-infrared II (NIR-II) photothermal enhanced SDT of tumor. Because of several oxygen vacancies and smaller size (~ 10 nm), the in-situ formed TiO2-x nanoparticles possessed narrow band gap (2.65 eV) and high surface area, and thus served as a charge trap to restrict charge recombination under ultrasound (US) activation, resulting in enhanced sonodynamic ROS generation. Moreover, Ti3C2 nanosheets induced extensive localized hyperthermia relieves tumor hypoxia by accelerating intratumoral blood flow and tumor oxygenation, and thus further strengthened the efficacy of SDT. Upon US/NIR-II laser dual-stimuli, Ti3C2@TiO2-x nanoplatform triggered substantial cellular killing in vitro and complete tumor eradication in vivo, without any tumor recurrence and systemic toxicity. Conclusion: Our work presents the promising design of photo/sono-responsive nanoplatform for cancer nanotheranostics. [ABSTRACT FROM AUTHOR]

• 3D printed PCL/CS scaffolds were developed with excellent bioactive compositions and controllable porous structures. • Alkaline phosphatase (ALP)-responsive scaffolds were developed through the combination of a hemicyanine dye and PCL/CS scaffolds. • The combination of near-infrared (NIR) fluorescence and photoacoustic imaging was achieved. • Non-invasive, real-time visualization of enhanced bone formation was achieved both in vitro and in vivo. Although numerous biomaterials have been fabricated as scaffolds for the application of tissue engineering, real-time non-invasive monitoring of in vivo bone regeneration is still a big challenge. Particularly, the early osteogenesis is difficult to detect using conventional imaging modalities, such as X-ray computed tomography (CT) and magnetic resonance imaging (MRI) due to the limited amount of neo-bone tissue. Herein we report on alkaline phosphatase (ALP)-responsive scaffolds, which are composed of a turn-on hemicyanine dye (LET-3) and a typical three dimensional (3D) printed bone tissue engineering scaffold (polycaprolactone/calcium silicate, PCL/CS), for real-time non-invasive monitoring of in vivo bone regeneration by near-infrared fluorescence (NIR-FL) and photoacoustic (PA) duplex imaging. ALP, an early-stage biomarker of bone formation, turns "on" the NIR-FL/PA signals of LET-3 in scaffolds both in vitro and in vivo. Thus, the osteogenic-associated bioactivity of LET-3 labeled scaffolds could be visualized by NIR-FL/PA dual-modal imaging. Our results provide a promising strategy for detecting neo-bone formation by the combination of ALP prober and bone tissue engineering scaffolds, which holds great potential for traceable tissue engineering. [ABSTRACT FROM AUTHOR]