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Hypoxia is one of the inherent characteristics of most solid tumors; the oxygen-dependent (O2) nature of photodynamic therapy (PDT) limits its clinical treatment against hypoxia tumors. Therefore, improving the oxygen partial pressure of hypoxic tumors is of great significance to improve the PDT effect. Herein, we synthesized the Ti3C2@Porphyridium nanobiohybrids (MX@Pr) by electrostatic self-assembly of photosynthetic oxygen-producing Porphyridium (Pr) and photosensitizer two-dimensional Ti3C2 (MX). Upon 660 nm laser irradiation, MX@Pr in the tumor region could increase the local oxygen level by in situ oxygen generation via Pr-mediated photosynthesis. The oxygen produced by Pr can receive the energy transferred by the excited photosensitizer MX to produce singlet oxygen (1O2), thus significantly enhancing the PDT efficacy of hypoxic tumors and inhibiting tumor growth. This study provides a PDT composite system, which shows the promising prospect of microbial nanomaterial composite systems in the field of biomedicine. [ABSTRACT FROM AUTHOR]

The utilization of alkyl radicals (•R) for hypoxic tumor therapy has great prospects due to its O 2 -independence and high reactivity. However, correlational initiators for in vivo activation remain scarce. Here, we report that ultrasound excitation of oleic acid-capped BaTiO 3 (OA@BaTiO 3 ) can result in an •R cascade and hence a means to conquer hypoxic tumors. Mechanistic studies find that the •R signal disappears when OA@BaTiO 3 undergoes acid washing post-treatment, which is a common procedure for removing the unwanted byproduct BaCO 3 . Combined with the infrared spectrum analysis, acid treatment was proven to weaken the peaks at 2840-2970 cm -1 characteristic of -CH 2 - and terminal -CH 3 stretching vibration of OA. There is compelling evidence that high temperature thermal oxidation of OA involves the generation of •R. Thus, acid washing is considered to remove the loosely bound yet catalytically active OA. And piezoelectric BaTiO 3 , a potential electron-hole redox catalyst, can sensitize these OA molecules and disintegrate them to •R. This unexpected discovery provides us with a distinctive mentality to seek diverse •R initiators for tumor ablation, as well as an additional perspective on the postprocessing of synthetic materials.

The effect of photodynamic therapy (PDT) is severely limited by tumor hypoxia and the short half-life of reactive oxygen species (ROS). Herein, we constructed a near-infrared (NIR) light-regulated PDT nanoplatform (TPP-UCNPs@MOF-Pt) consisting of an upconversion nanoparticle (UCNP) core and porphyrin-based metal-organic framework (MOF) shell with platinum nanoparticles (PtNPs) and a mitochondria-targeting triphenylphosphine (TPP) group on the surface. TPP-UCNPs@MOF-Pt could effectively relieve the tumor hypoxia by converting intracellular H 2 O 2 to oxygen (O 2 ) and elevated the ROS level to enhance PDT efficacy under NIR light irradiation. In addition, the mitochondria-targeting TPP-UCNPs@MOF-Pt was localized on the mitochondria, leading to severe depolarization of the mitochondrial membrane and activation of the apoptotic pathway, further amplifying the therapeutic efficacy. In vitro and in vivo experiments demonstrated that the greatly enhanced photodynamic therapeutic efficacy of TPP-UCNPs@MOF-Pt was achieved by combining relief of tumor hypoxia with mitochondrial targeting and NIR activation. This study provides a promising strategy for construction of an MOF-based multifunctional nanoplatform to address the current limitations of PDT treatment for hypoxic tumors.

How to efficiently synthesize toxic chemo-drugs in the hypoxia tumor microenvironment still faces a huge challenge. Herein, we have tailored engineered vehicle-free nanoreactors by coordination-driven co-assembly of photosensitizer indocyanine green (ICG), transition metal platinum (Pt), and nontoxic 1,5-dihydroxynaphthalene (DHN) to self-amplify O 2 and cascade chemo-drug synthesis in tumor cells for self-reinforcing hypoxic oncotherapy. Once vehicle-free nanoreactors are internalized into tumor cells, they show a serious instability that results in rapid disassembly and on-demand drug release under the stimuli of acidic lysosome and laser radiation. Notably, the released Pt can efficiently decompose the endogenous hydrogen peroxide (H 2 O 2 ) into O 2 to alleviate tumor hypoxia, which is conducive to enhancing the photodynamic therapy (PDT) efficiency of the released ICG. Complementarily, a large amount of the 1 O 2 generated by PDT can efficiently oxidize the released nontoxic DHN into the highly toxic chemo-drug juglone. Therefore, such vehicle-free nanoreactors can achieve intracellular on-demand cascade chemo-drug synthesis and self-reinforce photo-chemotherapeutic efficacy on the hypoxic tumor. On the whole, such a simple, flexible, efficient, and nontoxic therapeutic strategy will broaden the study of on-demand chemo-drug synthesis and hypoxic oncotherapy.

Conventional NO gas generation based on l-arginine (l-Arg) is usually dependent on H 2 O 2 and O 2 , both of which are very limited within the tumor microenvironment, thus greatly limiting l-Arg's therapeutic effect. Herein, a novel nanoplatform for efficiently triggering NO production based on ultrasound-induced piezocatalysis was developed, which was fabricated by coating amphiphilic poly-l-arginine (DSPE-PEG 2000 -Arg, DPA) on the piezoelectric material of barium titanate (BTO). The resulting BTO@DPA nanoparticles can efficiently generate H 2 O 2 , 1 O 2 , and O 2 via ultrasound-induced piezocatalysis based on BTO and oxidize the surface arginine to produce NO, which can even further interact with the reactive oxygen species (ROS) to produce more reactive peroxynitrite, thus inducing serious tumor cell apoptosis both in hypoxia and normoxia. After intravenous injection, BTO@DPA accumulated well at the tumor tissue at 4 h postinjection; later, ultrasound irradiation on the tumor not only achieved the best tumor inhibition rate of ∼70% but also completely inhibited tumor metastasis to the lungs via the alleviation of tumor hypoxia. Such a strategy was not dependent on the tumor microenvironment and can be well controlled by ultrasound irradiation, providing a simple and efficient therapy paradigm for hypoxic tumor.

Clinical radiation therapy (RT) is often hindered by the low radiation energy absorption coefficient and the hypoxic features of tumor tissues. Among the tremendous efforts devoted to overcoming the barriers to efficient RT, the application of hypoxic radiosensitizers and cell-cycle-specific chemotherapeutics has shown great potential. However, their effectiveness is often compromised by their limited bioavailability, especially in the hypoxic region, which plays a major role in radioresistance. Herein, to simultaneously improve the delivery efficacy of both hypoxic radiosensitizer and cell-cycle-specific drug, a gambogic acid (GA) metronidazole (MN) prodrug (GM) was designed and synthesized based on GA, a naturally occurring chemotherapeutic and multiple pathway inhibitor, and MN, a typical hypoxic radiosensitizer. In combination with MN-containing block copolymers, the prodrug nanosensitizer (NS) of GM was obtained. Owing to the bioreduction of MN, the as-designed prodrug could be efficiently delivered to hypoxic cells and act on mitochondria to cause the accumulation of reactive oxygen species. The strong G 2 /M phase arrest caused by the prodrug NS could further sensitize treated cells to external radiation under hypoxic conditions by increasing DNA damage and delaying DNA repair. After coadministration of the NS with a well-established tissue-penetrating peptide, efficient tumor accumulation, deep tumor penetration, and highly potent chemoradiotherapy could be achieved.

An oxygen-irrelevant free radicals generation strategy has shown great potential in hypoxic tumor therapy. However, insufficient tumor accumulation, nonspecific intracellular localization, and the presence of highly reductive mitochondrial glutathione (GSH) dramatically hamper the free radicals therapeutic efficacy. Herein, a hierarchical targeting system was constructed by Fe-doped polydiaminopyridine nanoshuttles, indocyanine green (ICG), and an oxygen-irrelevant radicals generator (AIPH) to possess a negative charge. An acid-specific charge-reverse capability of the shuttles was achieved to enhance cell uptake in the tumor microenvironment (TME). In addition, the iron release occurs only in the acidic TME, which can be used as acidity enhancers to strengthen the charge-reverse process, thereby leading to more efficient tumor internalization and deep penetration. Moreover, such a nanosystem has significantly improved the delivery efficiency of nanoshuttles (16.06%) in the tumor tissues at 24 h postinjection, much higher than that of naked Fe-doped polydiaminopyridine (6.59%). More importantly, the nanoshuttles enable simultaneously mitochondria targeting and corresponding GSH depleting capability to show advantages in free radicals-based therapy after charge reversion, leading to a powerful tumor inhibition rate (>95%). The prescence of iron could allow for magnetic resonance imaging, while ICG allowed for photoacoustic imaging and fluorescence imaging to guide the therapeutic process. The remarkable features of the nanoshuttles may open a new avenue to explore an oxygen-irrelevant free radicals generating system for accurate cancer theranostics.

Oxygen consumption but hypoxic tumor environment has been considered as the major obstacle in photodynamic therapy. Although oxygen-supplied strategies have been reported extensively, they still suffer from the complicated system and unsatisfied PDT efficiency. Herein, one-component layered nickel silicate nanoplatforms (LNS NPs) are successfully synthesized using natural vermiculite as the silica source, which can simultaneously supply oxygen (O 2 ) and generate superoxide radicals (O 2 -• ) under near-infrared irradiation. The appropriate electron band structure endows LNS NPs with attractive optical properties, where the bandgap edges determine the performance of redox activity and spectral response characteristic. Evidenced by both in vitro and in vivo investigations, LNS NPs can generate sufficient superoxide radicals under 660 nm laser irradiation to induce tumor cell apoptosis even in a severe hypoxic environment, which benefits from self-supplied oxygen. Besides, the photoacoustic oxy-hem imaging and histologic assay further demonstrated that the generated oxygen can relieve the inherent intratumoral hypoxia. Therefore, LNS NPs not only serve as superoxide radical generator but also produce oxygen to modulate hypoxia, suggesting that it can be used for superoxide radical-mediated photodynamic therapy with enhanced antitumor effect.

Light-driven endogenous water oxidation has been considered as an attractive and desirable way to obtain O 2 and reactive oxygen species (ROS) in the hypoxic tumor microenvironment. However, the use of a second near-infrared (NIR-II) light to achieve endogenous H 2 O oxidation to alleviate tumor hypoxia and realize deep hypoxic tumor phototherapy is still a challenge. Herein, novel plasmonic Ag-AgCl@Au core-shell nanomushrooms (NMs) were synthesized by the selective photodeposition of plasmonic Au at the bulge sites of the Ag-AgCl nanocubes (NCs) under visible light irradiation. Upon NIR-II light irradiation, the resulting Ag-AgCl@Au NMs could oxidize endogenous H 2 O to produce O 2 to alleviate tumor hypoxia. Almost synchronously, O 2 could react with electrons on the conduction band of the AgCl core to generate superoxide radicals (O 2 •- )for photodynamic therapy. Moreover, Ag-AgCl@Au NMs with an excellent photothermal performance could further promote the phototherapy effect. In vitro experimental results show that the resulting Ag-AgCl@Au NMs could significantly improve tumor hypoxia and enhance phototherapy against a hypoxic tumor. The present study provides a new strategy to design H in vivo experimental results show that the resulting Ag-AgCl@Au NMs could significantly improve tumor hypoxia and enhance phototherapy against a hypoxic tumor. The present study provides a new strategy to design H 2 O-activatable, O 2 - and ROS-evolving NIR II light-response nanoagents for the highly efficient and synergistic treatment of deep O 2 -deprived tumor tissue.

The synergistic nanotheranostics of reactive oxygen species (ROS) augment or phototherapy has been a promising method within synergistic oncotherapy. However, it is still hindered by sophisticated design and fabrication, lack of a multimodal synergistic effect, and hypoxia-associated poor photodynamic therapy (PDT) efficacy. Herein, a kind of porous shuttle-shape platinum (IV) methylene blue (Mb) coordination polymer nanotheranostics-loaded 10-hydroxycamptothecin (CPT) is fabricated to address the abovementioned limitations. Our nanoreactors possess spatiotemporally controlled O 2 self-supply, self-sufficient singlet oxygen ( 1 O 2 ), and outstanding photothermal effect. Once they are taken up by tumor cells, nanoreactors as a cascade catalyst can efficiently catalyze degradation of the endogenous hydrogen peroxide (H 2 O 2 ) into O 2 to alleviate tumor hypoxia. The production of O 2 can ensure enhanced PDT. Subsequently, under both stimuli of external red light irradiation and internal lysosomal acidity, nanoreactors can achieve the on-demand release of CPT to augment in situ mitochondrial ROS and highly efficient tumor ablation via phototherapy. Moreover, under the guidance of near-infrared (NIR) fluorescent imaging, our nanoreactors exhibit strongly synergistic potency for treatment of hypoxic tumors while reducing damages against normal tissues and organs. Collectively, shuttle-shape platinum-coordinated nanoreactors with augmented ROS capacity and enhanced phototherapy efficiency can be regarded as a novel tumor theranostic agent and further promote the research of synergistic oncotherapy.

Multifunctional gold (Au)-based nanomaterials with high atomic number (symbol Z) and strong absorbance in the second near-infrared window (NIR-II) property are emerging as promising candidates for tumor thermo-radiotherapy. The main limitations of applying Au-based nanomaterials to biomedical studies include the absence of active tumor-targeting ability, penetrating efficiency, and stability. In this study, we present a novel type of tumor cell-derived stellate plasmonic exosomes (TDSP-Exos) for penetrative targeted tumor NIR-II thermo-radiotherapy and photoacoustic imaging. The TDSP-Exos are abundantly and easily produced by the incubation of tumor cells with gold nanostars, based on which gold nanostars promote the exocytosis of exosomes from tumor cells. Compared with bare gold nanostars, the TDSP-Exos exhibit pronounced accumulation in deep tumor tissues and perform well in both PA imaging and NIR-II thermo-radiotherapy against the tumor. Moreover, the TDSP-Exos improve tumor hypoxia to enhanced radiotherapy by NIR-II photothermal therapy. This work indicates that the tumor cell-derived exosomes have the potential to function as a universal carrier of photothermal agents for targeted tumor NIR-II thermo-radiotherapy.

Tumor hypoxia severely limits the therapeutic efficacy of solid tumors in photodynamic therapy. One strategy is to develop photosensitizers with simultaneously high efficiency in photodynamic (PDT) and photothermal therapies (PTT) in a single natural-origin phototheranostic agent to overcome this problem. However, less attention has been paid to the natural-origin phototheranostic agent with high PDT and PTT efficiencies even though they have negligible side effects and are environmentally sustainable in comparison with many reported phototheranostic agents. In addition, almost all clinical applied photosensitizers are of natural origin so far. Herein, we synthesized a natural product-based hypocrellin derivative ( AETHB ), with a high singlet oxygen quantum yield of 0.64 as an efficient photosensitizer different from commercially available porphyrin-based photosensitizers. AETHB is further assembled with human serum albumin to construct nanoparticles ( HSA-AETHB NPs ) with a high photothermal conversion efficiency (more than 50%). As-prepared HSA-AETHB NPs have shown good water solubility and biocompatibility, pH and light stability, wide absorption (400-750 nm), and NIR emission centered at 710 nm. More importantly, HSA-AETHB NPs can be applied for fluorescent/photoacoustic dual-mode imaging and simultaneously highly efficient PDT/PTT in hypoxic solid tumors. Therefore, this natural-origin multifunctional phototheranostic agent is showing very promising for effective, precise, and safe cancer therapy in clinical applications.

Hypoxia, a ubiquitously aberrant phenomenon implicated in tumor growth, causes severe tumor resistance to therapeutic interventions. Instead of the currently prevalent solution through intratumoral oxygen supply, we put forward an "O 2 -economizer" concept by inhibiting the O 2 consumption of cell respiration to spare endogenous O 2 and overcome the hypoxia barrier. A nitric oxide (NO) donor responsible for respiration inhibition and a photosensitizer for photodynamic therapy (PDT) are co-loaded into poly(d,l-lactide- co-glycolide) nanovesicles to provide a PDT-specific O 2 economizer. Once accumulating in tumors and subsequently responding to the locally reductive environment, the carried NO donor undergoes breakdown to produce NO for inhibiting cellular respiration, allowing more O 2 in tumor cells to support the profound enhancement of PDT. Depending on the biochemical reallocation of cellular oxygen resource, this O 2 -economizer concept offers a way to address the important issue of hypoxia-induced tumor resistance to therapeutic interventions, including but not limited to PDT.

Radioresistance is one of the undesirable impediments in hypoxic tumors, which sharply diminishes the therapeutic effectiveness of radiotherapy and eventually results in the failure of their treatments. An attractive strategy for attenuating radioresistance is developing an ideal radiosensitization system with appreciable radiosensitization capacity to attenuate tumor hypoxia and reinforce radiotherapy response in hypoxic tumors. Therefore, we describe the development of Gd-containing polyoxometalates-conjugated chitosan (GdW 10 @CS nanosphere) as a radiosensitization system for simultaneous extrinsic and intrinsic radiosensitization, by generating an overabundance of cytotoxic reactive oxygen species (ROS) using high-energy X-ray stimulation and mediating the hypoxia-inducible factor-1a (HIF-1a) siRNA to down-regulate HIF-1α expression and suppress broken double-stranded DNA self-healing. Most importantly, the GdW 10 @CS nanospheres have the capacity to promote the exhaustion of intracellular glutathione (reduced GSH) by synergy W 6+ -triggered GSH oxidation for sufficient ROS generation, thereby facilitating the therapeutic efficiency of radiotherapy. As a result, the as-synthesized GdW 10 @CS nanosphere can overcome radioresistance of hypoxic tumors through a simultaneous extrinsic and intrinsic strategy to improve radiosensitivity. We have demonstrated GdW 10 @CS nanospheres with special radiosensitization behavior, which provides a versatile approach to solve the critical radioresistance issue of hypoxic tumors.

Hypoxia, a typical feature of solid tumors, remarkably restricts the efficiency of photodynamic therapy (PDT). Here, a carbon nitride (C3N4)-based multifunctional nanocomposite (PCCN) for light-driven water splitting was used to solve this problem. Carbon dots were first doped with C3N4 to enhance its red region absorption because red light could be used to trigger the in vivo water splitting process. Then, a polymer containing a protoporphyrin photosensitizer, a polyethylene glycol segment, and a targeting Arg-Gly-Asp motif was synthesized and introduced to carbon-dot-doped C3N4 nanoparticles. In vitro study showed that PCCN, thus obtained, could increase the intracellular O2 concentration and improve the reactive oxygen species generation in both hypoxic and normoxic environments upon light irradiation. Cell viability assay demonstrated that PCCN fully reversed the hypoxia-triggered PDT resistance, presenting a satisfactory growth inhibition of cancer cells in an O2 concentration of 1%. In vivo experiments also indicated that PCCN had superior ability to overcome tumor hypoxia. The use of water splitting materials exhibited great potential to improve the intratumoral oxygen level and ultimately reverse the hypoxia-triggered PDT resistance and tumor metastasis.