In this study, we developed a general method to decorate plasmonic gold nanorods (GNRs) with a CD44-targeting functional polymer, containing a hyaluronic acid (HA)-targeting moiety and a small molecule Glut1 inhibitor of diclofenac (DC), to obtain GNR/HA-DC. This nanosystem exhibited the superiority of selectively sensitizing tumor cells for photothermal therapy (PTT) by inhibiting anaerobic glycolysis. Upon specifically targeting CD44, sequentially time-dependent DC release could be achieved by the trigger of hyaluronidase (HAase), which abundantly existed in tumor tissues. The released DC depleted the Glut1 level in tumor cells and induced a cascade effect on cellular metabolism by inhibiting glucose uptake, blocking glycolysis, decreasing ATP levels, hampering heat shock protein (HSP) expression, and ultimately leaving malignant cells out from the protection of HSPs to stress (e.g., heat), and then tumor cells were more easy to kill. Owing to the sensitization effect of GNR/HA-DC, CD44 overexpressed tumor cells could be significantly damaged by PTT with an enhanced therapeutic efficiency in vitro and in vivo.

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Tumor hypoxia severely limits the efficacy of traditional photodynamic therapy (PDT). Here, a liposome-based nanoparticle (designated as LipoMB/CaO ) with O self-sufficient property for dual-stage light-driven PDT is demonstrated to address this problem. Through a short time irradiation, O activated by the photosensitizer methylene blue (MB) can induce lipid peroxidation to break the liposome, and enlarge the contact area of CaO with H O, resulting in accelerated O production. Accelerated O level further regulates hypoxic tumor microenvironment and in turn improves O generation by MB under another long time irradiation. In vitro and in vivo experiments also demonstrate the superior competence of LipoMB/CaO to alleviate tumor hypoxia, suppress tumor growth and antitumor metastasis with low side-effect. The O self-sufficient LipoMB/CaO nanoplatform with dual-stage light manipulation is a successful attempt for PDT against hypoxic tumor.

A multifunctional prodrug, designated as TPP‐L‐GEM, is fabricated to realize image‐guided in situ tumor photodynamic therapy (PDT) with red light activatable chemotherapy. Gemcitabine is conjugated with a fluorescent photosensitizer, meso‐tetraphenylporphyrin (TPP), by a reactive oxygen species cleavable thioketal linker. Under the irradiation of low‐energy red light, TPP can generate singlet oxygen and damage tumor cells by photodynamic therapy. Simultaneously, the thioketal linkage can be cleaved by singlet oxygen and result in a cascaded gemcitabine release, causing sustained cell damage by chemotherapy. With the combination of PDT and cascaded chemotherapy, TPP‐L‐GEM shows significant tumor therapeutic efficacy in vitro and in vivo. Furthermore, the inherent fluorescent property of TPP endows the TPP‐L‐GEM prodrug with noninvasive drug tracking capability, which is favorable for image‐guided tumor therapy.

Conventional photodynamic therapy (PDT) has limited applications in clinical cancer therapy due to the insufficient O 2 supply, inefficient reactive oxygen species (ROS) generation, and low penetration depth of light. In this work, a multifunctional nanoplatform, upconversion nanoparticles (UCNPs)@TiO 2 @ MnO 2 core/shell/sheet nanocomposites (UTMs), is designed and constructed to overcome these drawbacks by generating O 2 in situ, amplifying the content of singlet oxygen ( 1 O 2 ) and hydroxyl radical (·OH) via water-splitting, and utilizing 980 nm near-infrared (NIR) light to increase penetration depth. Once UTMs are accumulated at tumor site, intracellular H 2 O 2 is catalyzed by MnO 2 nanosheets to generate O 2 for improving oxygen-dependent PDT. Simultaneously, with the decomposition of MnO 2 nanosheets and 980 nm NIR irradiation, UCNPs can efficiently convert NIR to ultraviolet light to activate TiO 2 and generate toxic ROS for deep tumor therapy. In addition, UCNPs and decomposed Mn 2+ can be used for further upconversion luminescence and magnetic resonance imaging in tumor site. Both in vitro and in vivo experiments demonstrate that this nanoplatform can significantly improve PDT efficiency with tumor imaging capability, which will find great potential in the fight against tumor. Scheme 1. Schematic illustration of UTMs for O 2 self-supplemented and ROS circulating amplified PDT. A) Fabrication of UTMs nanoplatform by combining UCNPs@TiO 2 nanoparticles and MnO 2 nanosheets. B) EPR effect mediated tumor accumulation and cellular uptake of UTMs. C) Intracellular decomposition of MnO 2 nanosheets to produce O 2 and NIR-activated catalysis of TiO 2 nanoshells to induce ROS ( 1 O 2 and ·OH) generation via H 2 O 2 and H 2 O splitting reactions. D) The detailed mechanisms of circulating amplified ROS generation: NIR-activated energy transfer to emit UV light via UCNPs; UV-excited electrons transfer from valence band (VB) to conduction band (CB) of TiO 2 nanoshells to further catalyze O 2 and H 2 O to generate 1 O 2 , O 2 •− and ·OH; MnO 2 nanosheets-catalyzed production of O 2 via H 2 O 2 splitting to further enhance O 2 concentration, and finally intracellular superoxide dismutase (SOD) for converting O 2 •− back to O 2 and H 2 O 2 to put a perfect ending on ROS circulating amplified reactions. E) All the corresponding reactions of various components (MnO 2 , TiO 2 , and SOD) and their interrelations for circulating amplified ROS generation. www.afm-journal.de www.advancedsciencenews.com 1700626 (3 of 14)