Ultrasound with deep penetration depth and high security could be adopted in sonodynamic therapy (SDT) by activating sonosensitizers to generate cytotoxic reactive oxygen species (ROS). Herein, two-dimensional (2D) coordination nanosheets composed of Zn²⁺ and Tetrakis(4-carboxyphenyl) porphyrin (TCPP) are fabricated. While exhibiting greatly enhanced ultrasound-triggered ROS generation useful for noninvasive SDT, such Zn-TCPP 2D nanosheets show high loading capacity of oligodeoxynucleotides such as cytosine-phosphorothioate-guanine (CpG), which is a potent toll like receptor 9 (TLR9) agonist useful in activating immune responses. Highly effective SDT of primary tumors could release tumor-associated antigens, which working together with Zn-TCPP/CpG adjuvant nanosheets could function like whole-tumor-cell vaccines and trigger tumor-specific immune responses. Interestingly, ultrasound itself could strengthen anti-tumor immune responses by improving the tumor-infiltration of T cells and limiting regulatory T cells in the tumor microenvironment. Thus, SDT using Zn-TCPP/CpG nanosheets after destruction of primary tumors could induce potent antitumor immune responses to inhibit distant abscopal tumors without direct SDT treatment. Moreover, SDT with Zn-TCPP/CpG could trigger strong immunological memory effects to inhibit cancer recurrence after elimination of primary tumors. Therefore, the 2D coordination nanosheet may be a promising platform to deliver potent SDT-triggered immunotherapy for highly effective cancer treatment.

Electrodynamic therapy (EDT) is a conceptually new cancer treatment approach recently proposed by our group. During EDT, the electro-driven catalytic reaction would occur on the surface of platinum nanoparticles (PtNPs) to produce reactive oxygen species (ROS) under the direct current (DC) or square-wave alternating current (AC) electric field. To further extend the potential of EDT, we hereby designed mesoporous silica-based nanocomposites decorated with PtNPs and loaded with anticancer drug doxorubicin (DOX) for synergistic electrodynamic-chemotherapy. Such silica-based nanocomposites could enable homogenous killing of large-sized tumors (over 500 mm³) and realize remarkable tumor destruction efficacy at a relatively low quantity of electricity. To our best knowledge, this is the first study to combine EDT and chemotherapy to develop a synergetic nanoplatform, openning a new dimension for the design of other EDT-based anticancer strategies.

Nanoscale metal organic frameworks (NMOFs) with porous structure and inherent biodegradability are attractive nanomedicine platforms. In addition to conventional particulate NMOFs, two-dimensional (2D) NMOFs are emerging as a unique type of NMOFs which however have been relatively less explored for nanomedicine applications. Herein, 2D NMOFs composed of Zn²⁺ and tetrakis(4-carboxyphenyl) porphyrin (TCPP) are fabricated and functionalized with polyethylene glycol (PEG). Compared to their particulate counterpart, such 2D NMOFs show greatly increased drug loading capacity and enhanced light-triggered singlet oxygen production, promising for chemotherapy and photodynamic therapy (PDT), respectively. Utilizing the porphyrin structure of TCPP, our 2D NMOFs could be labeled with a diagnostic radioisotope, ^99mTc, for single photon emission computer tomography (SPECT) imaging, which reveals efficient tumor homing of those 2D NMOFs upon intravenous injection. While offering a remarkable synergistic in vivo antitumor effect for the combined chemo-PDT, such 2D NMOFs show efficient biodegradation and rapid renal clearance. Our work presents the great promise of 2D NMOFs for nanomedicine applications.

The use of near-infrared (NIR) light for photodynamic therapy (PDT) is a promising strategy to circumvent the limitations of current PDT, in which visible light with limited tissue penetration depth is usually used. In the present study, alkyl thiolated gold nanoclusters (AuNCs) were co-modified with human serum albumin (HSA) and catalase (CAT), and then employed as a multifunctional, optical, theranostic nano-agent. In the AuNC@HSA/CAT system, the AuNCs were able to produce singlet oxygen under excitation by a 1, 064-nm laser, which locates in the second NIR window (NIR-II), and featured much lower tissue absorption and scattering, enabling NIR-II-triggered PDT. The HSA coating greatly improved the physiological stability of the nanoparticles, which showed efficient tumor retention after intravenous injection, as revealed by detecting the AuNC fluorescence. Moreover, the presence of CAT in the nanoparticles triggered decomposition of tumor endogenous H₂O₂ to generate oxygen, thereby enhancing the efficacy of PDT by relieving tumor hypoxia. Compared with conventional PDT using visible light, NIR-II-triggered PDT exhibits remarkably increased tissue penetration. Thus, we developed a new type of photosensitizing nano-agent that simultaneously enables in vivo fluorescence imaging, tumor hypoxia relief, and NIR-II light-induced in vivo PDT in the treatment of cancer.

Recently, covalent-organic polymers (COPs), which covalently cross-link different types of organic molecules to form organic network structures, have received significant attention in various fields. However, the design of COPs that allows them to act as therapeutic agents remains to be explored. In the present study, a new class of COPs was fabricated by cross-linking the photosensitizer meso-tetra(p-hydroxyphenyl) porphine (THPP) to a chemotherapeutic pro-drug, cis-platinum (IV); the latter also acts as a reduction-responsive linker. After further conjugation with polyethylene glycol (PEG) in this one-pot reaction, we obtained THPP-Pt-PEG COPs, which can be stored in a lyophilized form and occur as stable nanoparticles in aqueous solution. The THPP-Pt-PEG COPs are effective in killing cancer cells through photodynamic treatment, and exhibited reduction-responsive degradation/drug release behaviors. Upon intravenous injection, the COPs, with a long blood circulation time, showed efficient tumor accumulation. Interestingly, we revealed that after injection of THPP-Pt-PEG COPs, tumors on mice exhibited greatly improved vascular perfusion and largely relieved tumor hypoxia, which favored subsequent photodynamic treatment. Hence, the combined chemo-photodynamic therapy of the COPs offers a remarkably improved therapeutic outcome compared to that with mono-therapies. This work presents a COP-based nanomedicine with high drug loading, lyophilizable formulation, prolonged blood half-life, efficient tumor passive homing, inherent biodegradability, and multiple therapeutic functions to achieve enhanced cancer combination therapy, with promise for clinical translation.

The photothermal therapy (PTT) technique is regarded as a promising method for cancer treatment. However, one of the obstacles preventing its clinical application is the non-degradability and biotoxicity of the existing heavy-metal and carbon-based therapeutic agents. Therefore, a PTT material with a high photothermal efficiency, low toxicity, and good biocompatibility is urgently wanted. Herein, we report a titanium oxide-based therapeutic agent with a high efficacy and low toxicity for the PTT process. We demonstrated that Magnéli-phase Ti₈O₁₅ nanoparticles fabricated by the arc-melting method exhibit > 98% absorption of near infrared light and a superior photothermal therapy effect in the in vivo mouse model. The Ti₈O₁₅ nanoparticle PTT material also shows a good biocompatibility and biosafety. Our study reveals Magnéli-phase titanium oxide as a new family of PTT agents and introduces new applications of titanium oxides for photothermal conversion.

The clinical translation of many inorganic nanomaterials is severely hampered by toxicity issues because of the long-term retention of these nanomaterials in the body. In this study, we developed a bio-clearable theranostic agent based on ultra-small MoS₂ nanodots, which were synthesized by a facile bottom-up approach through one-step solvothermal decomposition of ammonium tetrathiomolybdate. After modification by glutathione (GSH), the obtained MoS₂-GSH nanodots exhibited sub-10-nm hydrodynamic diameters without aggregation in various physiological buffers. Without showing appreciable in vitro toxicity, such MoS₂-GSH nanodots with strong near-infrared (NIR) absorbance could induce remarkable photothermal ablation of cancer cells. Upon intravenous (i.v.) injection, efficient tumor accumulation of MoS₂-GSH nanodots was observed by photoacoustic imaging, and further confirmed by analysis of the biodistribution of Mo. Notably, the MoS₂-GSH nanodots, in contrast to conventional MoS₂ nanoflakes with larger sizes, showed rather efficient body clearance via urine, where the majority of the injected dose was cleared within just seven days. Photothermal ablation of tumors on mice was then realized with the MoS₂-GSH nanodots, achieving excellent therapeutic efficacy. This study presents a new type of ultra-small nanoparticle with efficient tumor homing/treatment abilities, as well as rapid body clearance behavior, making it promising for cancer theranostics without long-term toxicity concerns.

Recently, photothermal therapy (PTT) has attracted tremendous attention because of its high efficacy in tumor ablation and minimal damage to normal tissues. While many inorganic nanomaterials, especially various gold nanostructures and nanocarbons, have been extensively explored for near-infrared (NIR) light triggered PTT in the past decade, a variety of organic photothermal agents have also emerged in recent years, aiming at replacing their inorganic counterparts which usually are not biodegradable. In this mini-review, we will summarize several typical classes of recently developed NIR-absorbing organic PTT nanoagents, which include NIR dye-containing micelles, porphysomes, protein-based agents, conjugated polymers, and organic/inorganic nanocomposites. The development of imaging-guided PTT and combination therapy will be introduced as well. Finally, the perspectives and challenges in the future development of PTT will be discussed.

Mesoporous silica nanoparticles (MSNs) have attracted tremendous attention in recent years as drug delivery carriers due to their large surface areas, tunable sizes, facile modification and considerable biocompatibility. In this work, we fabricate an interesting type of MSNs which are intrinsically doped with photosensitizing molecules, chlorin e6 (Ce6). By increasing the amount of Ce6 doped inside the silica matrix, it is found that the morphology of MSNs changes from spheres to rod-like shapes. The obtained Ce6-doped mesoporous silica nanorods (CMSNRs) are not only able to produce singlet oxygen for photodynamic therapy, but can also serve as a drug delivery platform with high drug loading capacity by utilizing their mesoporous structure. Compared to spherical nanoparticles, it is found that CMSNRs with a larger aspect ratio show much faster uptake by cancer cells. With doxorubicin (DOX) employed as a model drug, the combined photodynamic and chemotherapy is carried out, achieving synergistic anti-tumor effects both in vitro and in vivo. Our study presents a new design of an MSN-based drug delivery platform, which intrinsically is fluorescent and able to serve as a photodynamic agent, promising for future imaging-guided combination therapy of cancer.

Detection of circulating tumor cells (CTCs) plays an important role in cancer diagnosis and prognosis. In this study, aptamer-conjugated upconversion nanoparticles (UCNPs) are used for the first time as nanoprobes to recognize tumor cells, which are then enriched by attaching with magnetic nanoparticles (MNPs) and placing in the presence of a magnetic field. Owing to the autofluorescencefree nature of upconversion luminescence imaging, as well as the use of magnetic separation to further reduce background signals, our technique allows for highly sensitive detection and collection of small numbers of tumor cells spiked into healthy blood samples, and shows promise for CTC detection in medical diagnostics.