Photosensitizer Decorated Red Blood Cells as an Ultrasensitive Light-Responsive Drug Delivery System

Red blood cells (RBCs) have been widely explored as a natural drug delivery system (DDS) owing to their inherent biocompatibility and large internal cavities to load various types of functional molecules. Herein, we uncover that a photosensitizer, chlorin e6 (Ce6), could be decorated into the membrane of RBCs upon simple mixing, without affecting the membrane integrity and stability in dark. Upon light irradiation with a rather low power density, the singlet oxygen generated by Ce6 would lead to rather efficient disruption of RBC membrane. With doxorubicin (DOX), a typical chemotherapy drug, as the model, we engineer a unique type of light-responsive RBC-based DDS by decorating Ce6 on the cell membrane and loading DOX inside cells. The light triggered cell membrane breakdown would thus trigger instant release of DOX, enabling light-controlled chemotherapy with great specificity. Beyond that our RBC system could also be utilized for loading of larger biomolecules such as enzymes, whose release as well as catalytic function is also controlled by light. Our work thus presents a unique type of biocompatible cell-based DDS that can be precisely controlled by mild external stimuli, promising not only for cancer therapy but also for other potential applications in biotechnologies

Theranostic Liposomes with Hypoxia-Activated Prodrug to Effectively Destruct Hypoxic Tumors Post-Photodynamic Therapy

Photodynamic therapy (PDT), a noninvasive cancer therapeutic method triggered by light, would lead to severe tumor hypoxia after treatment. Utilizing a hypoxia-activated prodrug, AQ4N, which only shows toxicity to cancer cells under hypoxic environment, herein, a multipurpose liposome is prepared by encapsulating hydrophilic AQ4N and hydrophobic hexadecylamine conjugated chlorin e6 (<i>h</i>Ce6), a photosensitizer, into its aqueous cavity and hydrophobic bilayer, respectively. After chelating a ⁶⁴Cu isotope with Ce6, the obtained AQ4N-⁶⁴Cu-<i>h</i>Ce6-liposome is demonstrated to be an effective imaging probe for <i>in vivo</i> positron emission tomography, which together with <i>in vivo</i> fluorescence and photoacoustic imaging uncovers efficient passive homing of those liposomes after intravenous injection. After being irradiated with the 660 nm light-emitting diode light, the tumor bearing mice with injection of AQ4N-<i>h</i>Ce6-liposome show severe tumor hypoxia, which in turn would trigger activation of AQ4N, and finally contributes to remarkably improved cancer treatment outcomes <i>via</i> sequential PDT and hypoxia-activated chemotherapy. This work highlights a liposome-based theranostic nanomedicine that could utilize tumor hypoxia, a side effect of PDT, to trigger chemotherapy, resulting in greatly improved efficacy compared to conventional cancer PDT

Graphene-Based Nanocomposite As an Effective, Multifunctional, and Recyclable Antibacterial Agent

The development of new antibacterial agents that are highly effective are of great interest. Herein, we present a recyclable and synergistic nanocomposite by growing both iron oxide nanoparticles (IONPs) and silver nanoparticles (AgNPs) on the surface of graphene oxide (GO), obtaining GO-IONP-Ag nanocomposite as a novel multifunctional antibacterial material. Compared with AgNPs, which have been widely used as antibacterial agents, our GO-IONP-Ag shows much higher antibacterial efficiency toward both Gram-negative bacteria <i>Escherichia coli</i> (<i>E. coli</i>) and Gram-positive bacteria <i>Staphylococcus aureus</i> (<i>S. aureus</i>). Taking the advantage of its strong near-infrared (NIR) absorbance, photothermal treatment is also conducted with GO-IONP-Ag, achieving a remarkable synergistic antibacterial effect to inhibit <i>S. aureus</i> at a rather low concentration of this agent. Moreover, with magnetic IONPs existing in the composite, we can easily recycle GO-IONP-Ag by magnetic separation, allowing its repeated use. Given the above advantages as well as its easy preparation and cheap cost, GO-IONP-Ag developed in this work may find potential applications as a useful antibacterial agent in the areas of healthcare and environmental engineering

Near-Infrared-Triggered Photodynamic Therapy with Multitasking Upconversion Nanoparticles in Combination with Checkpoint Blockade for Immunotherapy of Colorectal Cancer

While immunotherapy has become a highly promising paradigm for cancer treatment in recent years, it has long been recognized that photodynamic therapy (PDT) has the ability to trigger antitumor immune responses. However, conventional PDT triggered by visible light has limited penetration depth, and its generated immune responses may not be robust enough to eliminate tumors. Herein, upconversion nanoparticles (UCNPs) are simultaneously loaded with chlorin e6 (Ce6), a photosensitizer, and imiquimod (R837), a Toll-like-receptor-7 agonist. The obtained multitasking UCNP-Ce6-R837 nanoparticles under near-infrared (NIR) irradiation with enhanced tissue penetration depth would enable effective photodynamic destruction of tumors to generate a pool of tumor-associated antigens, which in the presence of those R837-containing nanoparticles as the adjuvant are able to promote strong antitumor immune responses. More significantly, PDT with UCNP-Ce6-R837 in combination with the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint blockade not only shows excellent efficacy in eliminating tumors exposed to the NIR laser but also results in strong antitumor immunities to inhibit the growth of distant tumors left behind after PDT treatment. Furthermore, such a cancer immunotherapy strategy has a long-term immune memory function to protect treated mice from tumor cell rechallenge. This work presents an immune-stimulating UCNP-based PDT strategy in combination with CTLA-4 checkpoint blockade to effectively destroy primary tumors under light exposure, inhibit distant tumors that can hardly be reached by light, and prevent tumor reoccurrence <i>via</i> the immune memory effect

Nanoscale Metal–Organic Particles with Rapid Clearance for Magnetic Resonance Imaging-Guided Photothermal Therapy

Nanoscale metal–organic particles (NMOPs) are constructed from metal ions and organic bridging ligands <i>via</i> the self-assembly process. Herein, we fabricate NMOPs composed of Mn²⁺ and a near-infrared (NIR) dye, IR825, obtaining Mn-IR825 NMOPs, which are then coated with a shell of polydopamine (PDA) and further functionalized with polyethylene glycol (PEG). While Mn²⁺ in such Mn-IR825@PDA–PEG NMOPs offers strong contrast in <i>T</i>₁-weighted magnetic resonance (MR) imaging, IR825 with strong NIR optical absorbance shows efficient photothermal conversion with great photostability in the NMOP structure. Upon intravenous injection, Mn-IR825@PDA–PEG shows efficient tumor homing together with rapid renal excretion behaviors, as revealed by MR imaging and confirmed by biodistribution measurement. Notably, when irradiated with an 808 nm laser, tumors on mice with Mn-IR825@PDA–PEG injection are completely eliminated without recurrence within 60 days, demonstrating the high efficacy of photothermal therapy with this agent. This study demonstrates the use of NMOPs as a potential photothermal agent, which features excellent tumor-targeted imaging and therapeutic functions, together with rapid renal excretion behavior, the latter of which would be particularly important for future clinical translation of nanomedicine

Smart Nanoreactors for pH-Responsive Tumor Homing, Mitochondria-Targeting, and Enhanced Photodynamic-Immunotherapy of Cancer

Photodynamic therapy (PDT) is an oxygen-dependent light-triggered noninvasive therapeutic method showing many promising aspects in cancer treatment. For effective PDT, nanoscale carriers are often needed to realize tumor-targeted delivery of photosensitizers, which ideally should further target specific cell organelles that are most vulnerable to reactive oxygen species (ROS). Second, as oxygen is critical for PDT-induced cancer destruction, overcoming hypoxia existing in the majority of solid tumors is important for optimizing PDT efficacy. Furthermore, as PDT is a localized treatment method, achieving systemic antitumor therapeutic outcomes with PDT would have tremendous clinical values. Aiming at addressing the above challenges, we design a unique type of enzyme-encapsulated, photosensitizer-loaded hollow silica nanoparticles with rationally designed surface engineering as smart nanoreactors. Such nanoparticles with pH responsive surface coating show enhanced retention responding to the acidic tumor microenvironment and are able to further target mitochondria, the cellular organelle most sensitive to ROS. Meanwhile, decomposition of tumor endogenous H₂O₂ triggered by those nanoreactors would lead to greatly relieved tumor hypoxia, further favoring in vivo PDT. Moreover, by combining our nanoparticle-based PDT with check-point-blockade therapy, systemic antitumor immune responses could be achieved to kill nonirradiated tumors 1–2 cm away, promising for metastasis inhibition

Renal-Clearable Ultrasmall Coordination Polymer Nanodots for Chelator-Free ⁶⁴Cu-Labeling and Imaging-Guided Enhanced Radiotherapy of Cancer

Developing tumor-homing nanoparticles with integrated diagnostic and therapeutic functions, and meanwhile could be rapidly excreted from the body, would be of great interest to realize imaging-guided precision treatment of cancer. In this study, an ultrasmall coordination polymer nanodot (CPN) based on the coordination between tungsten ions (W^VI) and gallic acid (W-GA) was developed <i>via</i> a simple method. After polyethylene glycol (PEG) modification, PEGylated W-GA (W-GA-PEG) CPNs with an ultrasmall hydrodynamic diameter of 5 nm were rather stable in various physiological solutions. Without the need of chelator molecules, W-GA-PEG CPNs could be efficiently labeled with radioisotope ⁶⁴Cu²⁺, enabling positron emission tomography (PET) imaging, which reveals efficient tumor accumulation and rapid renal clearance of W-GA-PEG CPNs upon intravenous injection. Utilizing the radio-sensitizing function of tungsten with strong X-ray absorption, such W-GA-PEG CPNs were able to greatly enhance the efficacy of cancer radiotherapy in inhibiting the tumor growth. With fast clearance and little long-term body retention, those W-GA-PEG CPNs exhibited no appreciable <i>in vivo</i> toxicity. This study presents a type of CPNs with excellent imaging and therapeutic abilities as well as rapid renal clearance behavior, promising for further clinic translation

Synthesis of Hollow Biomineralized CaCO₃–Polydopamine Nanoparticles for Multimodal Imaging-Guided Cancer Photodynamic Therapy with Reduced Skin Photosensitivity

The development of activatable nanoplatforms to simultaneously improve diagnostic and therapeutic performances while reducing side effects is highly attractive for precision cancer medicine. Herein, we develop a one-pot, dopamine-mediated biomineralization method using a gas diffusion procedure to prepare calcium carbonate-polydopamine (CaCO₃–PDA) composite hollow nanoparticles as a multifunctional theranostic nanoplatform. Because of the high sensitivity of such nanoparticles to pH, with rapid degradation under a slightly acidic environment, the photoactivity of the loaded photosensitizer, i.e., chlorin e6 (Ce6), which is quenched by PDA, is therefore increased within the tumor under reduced pH, showing recovered fluorescence and enhanced singlet oxygen generation. In addition, due to the strong affinity between metal ions and PDA, our nanoparticles can bind with various types of metal ions, conferring them with multimodal imaging capability. By utilizing pH-responsive multifunctional nanocarriers, effective in vivo antitumor photodynamic therapy (PDT) can be realized under the precise guidance of multimodal imaging. Interestingly, at normal physiological pH, our nanoparticles are quenched and show much lower phototoxicity to normal tissues, thus effectively reducing skin damage during PDT. Therefore, our work presents a unique type of biomineralized theranostic nanoparticles with inherent biocompatibility, multimodal imaging functionality, high antitumor PDT efficacy, and reduced skin phototoxicity