Polymer-DNA Carriers Co-Deliver Photosensitizer and siRNA for Light-Promoted Gene Transfection and Hypoxia-Relieved Photodynamic Therapy.

Photochemical internalization is an efficient strategy relying on photodynamic reactions to promote siRNA endosomal escape for the success of RNA-interference gene regulation, which makes gene-photodynamic combined therapy highly synergistic and efficient. However, it is still desired to explore capable carriers to improve the delivery efficiency of the immiscible siRNA and organic photosensitizers simultaneously. Herein, we employ a micellar nanostructure (PSNA) self-assembled from polymer-DNA molecular chimeras to fulfill this task. PSNA can plentifully load photosensitizers in its hydrophobic core simply by the nanoprecipitation method. Moreover, it can organize siRNA self-assembly by the densely packed DNA shell, which leads to a higher loading capacity than the typical electrostatic condensation method. The experimental results prove that this PSNA carrier can greatly facilitate siRNA escape from the endosome/lysosome and enhance transfection. Accordingly, the PSNA-administrated therapy exhibits a significantly improved anti-tumor efficacy owing to the highly efficient co-delivery capability.

Translation, cultural adaptation, and validation of Numerical Pain Rating Scale and Global Rating of Change in Tibetan musculoskeletal trauma patients.

Tibetan-speaking patients seeking care in predominantly Mandarin-speaking healthcare settings frequently face communication barriers, leading to potential disparities and difficulties in accessing care. To address this issue, we translated, culturally adapted, and validated the Numerical Pain Rating Scale (NPRS) and the Global Rating of Change (GRoC) into Tibetan (NPRS-Tib and GRoC-Tib), aiming to facilitate cross-linguistic and cross-cultural interactions while examining potential challenges in the adaptation process. Using standard translation-backward translation methods, expert review, pilot testing, and validation through a cross-sectional study with a short-term longitudinal component, we engaged 100 Tibetan patients with musculoskeletal trauma for psychometric validation, including 37 women (aged 22-60 years, mean age 39.1 years). The NPRS-Tib and GRoC-Tib exhibited outstanding psychometric properties, with an Intraclass Correlation Coefficient (ICC) of 0.983 for NPRS-Tib indicating superb test-retest reliability, and expert review confirming good content validity for both instruments. A Spearman's correlation coefficient (Rho) of -0.261 (P = 0.0087) revealed a significant, albeit weak, correlation between changes in NPRS-Tib scores and GRoC-Tib scores. The adaptation process also presented notable challenges, including translation discrepancies from translators' diverse backgrounds and levels of expertise, ambiguity in scale options, and the lack of established tools for criterion validity assessment in Tibetan.

Biologically produced and metal-organic framework delivered dual-cut CRISPR/Cas9 system for efficient gene editing and sensitized cancer therapy.

Manipulation of the lactate metabolism is an efficient way for cancer treatment given its involvement in cancer development, metastasis, and immune escape. However, most of the inhibitors of lactate transport carriers suffer from poor specificity. Herein, we use the CRISPR/Cas9 system to precisely downregulate the monocarboxylate carrier 1 (MCT1) expression. To avoid the self-repairing during the gene editing process, a dual-Cas9 ribonucleoproteins (duRNPs) system is generated using the biological fermentation method and delivered into cells by the zeolitic imidazolate framework-8 (ZIF-8) nanoparticles, enabling precise removal of a specific DNA fragment from the genome. For efficient cancer therapy, a specific glucose transporter 1 inhibitor (BAY-876) is co-delivered with the duRNPs, forming BAY/duRNPs@ZIF-8 nanoparticle. ZIF-8 nanoparticles can deliver the duRNPs into cells within 1 h, which efficiently downregulates the MCT1 expression, and prohibits lactate influx. Through simultaneous inhibition of the lactate and glucose influx, BAY/duRNPs@ZIF-8 prohibits ATP generation, arrests cell cycle, inhibits cell proliferation, and finally induces cellular apoptosis both in vitro and in vivo. Consequently, we demonstrate that the biologically produced duRNPs delivered into cells by the nonviral ZIF-8 carrier have expanded the CRISPR/Cas gene editing toolbox and elevated the gene editing efficiency, which will promote biological studies and clinical applications. STATEMENT OF SIGNIFICANCE: The CRISPR/Cas9 system, widely used as an efficient gene editing tool, faces a challenge due to cells' ability to self-repair. To address this issue, a strategy involving dual-cutting of the genome DNA has been designed and implemented. This strategy utilizes biologically produced dual-ribonucleoproteins delivered by a metal-organic framework. The effectiveness of this dual-cut CRISPR-Cas9 system has been demonstrated through a therapeutic approach targeting the simultaneous inhibition of lactate and glucose influx in cancer cells. The utilization of the dual-cut gene editing strategy has provided valuable insights into gene editing and expanded the toolbox of the CRISPR/Cas-based gene editing system. It has the potential to enable more efficient and precise manipulation of specific protein expression in the future.

Bromine Substitution Improves the Photothermal Performance of π-Conjugated Phototheranostic Molecules.

NIR-II fluorescence imaging-guided photothermal therapy (PTT) has been widely investigated due to its great application potential in tumor theranostics. PTT is an effective and non-invasive tumor treatment method that can adapt to tumor hypoxia; nevertheless, simple and effective strategies are still desired to develop new materials with excellent PTT properties to meet clinical requirements. In this work, we developed a bromine-substitution strategy to enhance the PTT of A-D-A'-D-A π-conjugated molecules. The experimental results reveal that bromine substitution can notably enhance the absorptivity (ϵ) and photothermal conversion efficiency (PCE) of the π-conjugated molecules, resulting in the brominated molecules generating two times more heat (ϵ808 nm ×PCE) than their unsubstituted counterpart. We disclose that the enhanced photothermal properties of bromine-substituted π-conjugated molecules are a combined outcome of the heavy-atom effect, enhanced ICT effect, and more intense bromine-mediate intermolecular π-π stacking. Finally, the NIR-II tumor imaging capability and efficient PTT tumor ablation of the brominated π-conjugated materials demonstrate that bromine substitution is a promising strategy for developing future high-performance NIR-II imaging-guided PTT agents.

The Balance Effect of π-π Electronic Coupling on NIR-II Emission and Photodynamic Properties of Highly Hydrophobic Conjugated Photosensitizers.

Deep NIR organic phototheranostic molecules generally have large π-conjugation structures and show highly hydrophobic properties, thus, forming strong π-π stacking in the aqueous medium, which will affect the phototheranostic performance. Herein, an end-group strategy is developed to lift the performance of NIR-II emitting photosensitizers. Extensive characterizations reveal that the hydrogen-bonding interactions of the hydroxyl end group can induce a more intense π-π electronic coupling than the chlorination-mediated intermolecular forces. The results disclose that π-π stacking will lower fluorescence quantum yield but significantly benefit the photodynamic therapy (PDT) efficiency. Accordingly, an asymmetrically substituted derivative (BTIC-δOH-2Cl) is developed, which shows balanced phototheranostic properties with excellent PDT efficiency (14.6 folds of ICG) and high NIR-II fluorescence yield (2.27%). It proves the validity of the end-group strategy on controlling the π-π interactions and rational tuning the performance of NIR-II organic phototheranostic agents.

Ultra-stable MOF@MOF nanoplatform for photodynamic therapy sensitized by relieved hypoxia due to mitochondrial respiration inhibition.

Metal-organic frameworks (MOFs) with periodically arranged porphyrinic linkers avoiding the self-quenching issue of porphyrins in photodynamic therapy (PDT) have been widely applied. However, the porphyrinic MOFs still face challenges of poor stability under physiological conditions and limited photodynamic efficiency by the hypoxia condition of tumors. Herein, we fabricate the MOF@MOF structure with a protective MOF shell to improve the stability and relieve the hypoxia condition of tumors for sensitized PDT. Under protection of the MOF shell, the MOF@MOF structure can keep intact for 96 h under physiological conditions. Consequently, the tumoral accumulation efficiency is two folds of the MOF core. Furthermore, the MOF shell decomposes under acidic environment, and the loaded inhibitor of mitochondria pyruvate carrier (7-amino carboxycoumarins-2, 7ACC2) will be released. 7ACC2 inhibits the mitochondrial pyruvate influx and simultaneously blocks glucose and lactate from fueling the mitochondrial respiration, thereupon relieving the hypoxia condition of tumors. Under a 5-min laser irradiation, the 7ACC2 carrying MOF@MOF nanoplatforms induced doubled cellular apoptosis and reduced 70% of the tumor growth compared with the cargo-free MOF@MOF. In summary, the design of this stable and hypoxia self-relievable MOF@MOF nanoplatform will enlighten the future development of MOF-based nanomedicines and PDT. STATEMENT OF SIGNIFICANCE: Though widely used for photodynamic therapy (PDT) in previous studies, porphyrinic metal-organic frameworks (MOFs) still face challenges in poor stability under physiological conditions and limited photodynamic efficiency due to the hypoxia condition of tumors. In order to solve these problems, (1) we develop the MOF@MOF strategy to improve the physiological stability; (2) an inhibitor of mitochondria pyruvate carrier, 7-amino carboxycoumarins-2 (7ACC2), is loaded to inhibit the mitochondrial pyruvate influx and simultaneously block glucose and lactate from fueling the mitochondrial respiration, thereupon relieving the hypoxia condition of tumors. In comparison with previous studies, our strategy simultaneously improves stability and overcomes the limited PDT efficiency in the hypoxia tumor tissue, which will enlighten the future development of MOF-based nanomedicines and PDT.

Chlorination-Mediated π-π Stacking Enhances the Photodynamic Properties of a NIR-II Emitting Photosensitizer with Extended Conjugation.

NIR-II-emitting photosensitizers (PSs) have attracted great research interest due to their promising clinical applications in imaging-guided photodynamic therapy (PDT). However, it is still challenging to realize highly efficient PDT on NIR-II PSs. In this work, we develop a chlorination-mediated π-π organizing strategy to improve the PDT of a PS with conjugation-extended A-D-A architecture. The significant dipole moment of the carbon-chlorine bond and the strong intermolecular interactions of chlorine atoms bring on compact π-π stacking in the chlorine-substituted PS, which facilitates energy/charge transfer and promotes the photochemical reactions of PDT. Consequently, the resultant NIR-II emitting PS exhibits a leading PDT performance with a yield of reactive oxygen species higher than that of previously reported long-wavelength PSs. These findings will enlighten the future design of NIR-II emitting PSs with enhanced PDT efficiency.

One-Pot Rapid Synthesis of Cu2+-Doped GOD@MOF to Amplify the Antitumor Efficacy of Chemodynamic Therapy.

Chemodynamic therapy (CDT) relies on the transformation of intracellular hydrogen peroxide (H2O2) to hydroxyl radicals (·OH) with higher toxicity under the catalysis of Fenton/Fenton-like reagents, which amplifies the oxidative stress and induces significant cellular apoptosis. However, the CDT efficacy is generally limited by the overexpressed GSH and insufficient endogenous H2O2 in tumors. Co-delivery of Cu2+ and glucose oxidase (GOD) can lead to a Cu2+/Cu+ circulation to realize GSH depletion and amplify the Fenton-like reaction. pH-responsive metal-organic frameworks (MOFs) are the optical choice to deliver Fenton/Fenton-like ions to tumors. However, considering that the aqueous condition is requisite for GOD encapsulation, it is challenging to abundantly dope Cu2+ in ZIF-8 MOF nanoparticles in aqueous conditions due to the ease of precipitation and enlarged crystal size. In this work, a robust one-pot biomimetic mineralization method using excessive ligand precursors in aqueous conditions is developed to synthesize GOD@Cu-ZIF-8. Copper ions abundantly doped to the GOD@Cu-ZIF-8 can eliminate GSH to produce Cu+, which is further proceeded to the Fenton-like reaction in the presence of GOD-catalyzed H2O2. Through breaking the tumor microenvironment homeostasis and producing an enhanced CDT effect, the promising antitumor capability of GOD@Cu-ZIF-8 was evidenced by the experiments both in vitro and in vivo.

NIR-II Luminescent and Multi-Responsive Rare Earth Nanocrystals for Improved Chemodynamic Therapy.

Chemodynamic therapy (CDT) based on the Fe2+-mediated Fenton reaction can amplify intracellular oxidative stress by producing toxic •OH. However, the high-dose need for Fe2+ delivery in tumors and its significant cytotoxicity to normal tissues set a challenge. Therefore, a controllable delivery to activate the Fenton reaction and enhance Fe2+ tumor accumulation has become an approach to solve this conflict. Herein, we report a rare-earth-nanocrystal (RENC)-based Fe2+ delivery system using light-control techniques and DNA nanotechnology to realize programmable Fe2+ delivery. Ferrocenes, the source of Fe2+, are modified on the surface of RENCs through pH-responsive DNAs, which are further shielded by a PEG layer to elongate blood circulation and "turn off" the cytotoxicity of ferrocene. The up-/down-conversion dual-mode emissions of RENCs endow the delivery system with both capabilities of diagnosis and delivery control. The down-conversion NIR-II fluorescence can locate tumors. Consequently, up-conversion UV light spatiotemporally activates the catalytic activity of Fe2+ by shedding off the protective PEG layer. The exposed ferrocene-DNAs not only can "turn on" Fenton catalytic activity but also respond to tumor acidity, driving cross-linking and enhanced Fe2+ enrichment in tumors by 4.5-fold. Accordingly, this novel design concept will be inspiring for developing CDT nanomedicines in the future.

A nanotherapeutic system for gastric cancer suppression by synergistic chemotherapy and immunotherapy based on iPSCs and DCs exosomes.

BACKGROUND: Chemotherapeutic drugs, the indispensable therapy in the treatment of gastric cancer, contain many problems such as high organ toxicity and insufficient therapeutic effect. The development of nanodrug delivery carriers with both tumor targeting function and immune stimulation ability possesses the potential to remedy these practical defects. METHODS AND RESULTS: In this study, a tumor targeting nanosystem that combines chemotherapy with immunotherapy was applied to the treatment and prognosis of gastric cancer. The fusion vector of iPSCs and DCs exosomes, which simultaneously possess the ability of tumor targeting and immune factor recruitment, effectively improved the in vivo efficacy of chemotherapy drugs and released the suppressed T lymphocytes under the action of modified PD-1 antibody to dredge the immunotherapy process. In addition, extensive recruitment of immune cells to clean the environment while exposing vast tumor antigens efficiently amplified the anti-tumor immune effect and ensured the good prognosis. CONCLUSIONS: Nanodrug delivery system DOX@aiPS-DCexo could effectively inhibit the expansion process of gastric cancer MFC through synergistic chemotherapy and immunotherapy and demonstrated the capacity of improving prognosis. Scheme: schematic illustration of the nanostructure DOX@aiPS-DCexo and the mechanism of action.

A pH-responsive T1-T2 dual-modal MRI contrast agent for cancer imaging.

Magnetic resonance imaging (MRI) is a non-invasive imaging technology to diagnose health conditions, showing the weakness of low sensitivity. Herein, we synthesize a contrast agent, SPIO@SiO2@MnO2, which shows decreased T1 and T2 contrast intensity in normal physiological conditions. In the acid environment of tumor or inflamed tissue, the manganese dioxide (MnO2) layer decomposes into magnetically active Mn2+ (T1-weighted), and the T1 and T2 signals are sequentially recovered. In addition, both constrast quenching-activation degrees of T1 and T2 images can be accurately regulated by the silicon dioxide (SiO2) intermediate layer between superparamagnetic iron oxide (SPIO) and MnO2. Through the "dual-contrast enhanced subtraction" imaging processing technique, the contrast sensitivity of this MRI contrast agent is enhanced to a 12.3-time difference between diseased and normal tissue. Consequently, SPIO@SiO2@MnO2 is successfully applied to trace the tiny liver metastases of approximately 0.5 mm and monitor tissue inflammation.

Low-Power Magnetic Resonance-Guided Focused Ultrasound Tumor Ablation upon Controlled Accumulation of Magnetic Nanoparticles by Cascade-Activated DNA Cross-Linkers.

Magnetic resonance-guided focused ultrasound (MRgFUS) is a promising non-invasive surgical technique with spatial specificity and minimal off-target effects. Despite the expanding clinical applications, the major obstacles associated with MRgFUS still lie in low magnetic resonance imaging (MRI) sensitivity and safety issues. High ultrasound power is required to resist the energy attenuation during the delivery to the tumor site and may cause damage to the surrounding healthy tissues. Herein, a surface modification strategy is developed to simultaneously strengthen MRI and ultrasound ablation of MRgFUS by prolonging Fe3O4 nanoparticles' blood circulation and tumor-environment-triggered accumulation and retention at the tumor site. Specifically, reactive oxygen species-labile methoxy polyethylene glycol and pH-responsive DNA cross-linkers are modified on the surface of Fe3O4 nanoparticles, which can transform nanoparticles into aggregations through the cascade responsive reactions at the tumor site. Notably, DNA is selected as the pH-responsive cross-linker because of its superior biocompatibility as well as the fast and sensitive response to the weak acidity of 6.5-6.8, corresponding to the extracellular pH of tumor tissues. Due to the significantly enhanced delivery and retention amount of Fe3O4 nanoparticles at the tumor site, the MRI sensitivity was enhanced by 1.7-fold. In addition, the ultrasound power was lowered by 35% to reach a sufficient thermal ablation effect. Overall, this investigation demonstrates a feasible resolution to promote the MRgFUS treatment by enhancing the therapeutic efficacy and reducing the side effects, which will be helpful to guide the clinical practice in the future.

Morphologically Tunable Supramolecular Rectangular Microsheet and Microsaw Constructed by Hierarchical Self-Assembly Based on Hydrogen Bonds.

An amino acid derivative, thiophene (TDAV), as new building blocks for 2D supramolecular assembly is designed. Various square and rectangular microsheets are achieved and the aspect ratios are precisely regulated by controlling the polarity of cosolvent or water content. By the introduction of chirality, the novel microsaw is also achieved. It provides a new approach to prepare various kinds of unique supramolecular 2D materials with controllable shapes and sizes for future biological applications.

Light-Harvesting Fluorescent Spherical Nucleic Acids Self-Assembled from a DNA-Grafted Conjugated Polymer for Amplified Detection of Nucleic Acids.

The ultralow concentration of nucleic acids in complex biological samples requires fluorescence probes with high specificity and sensitivity. Herein, a new kind of spherical nucleic acids (SNAs) is developed by using fluorescent π-conjugated polymers (FCPs) as a light-harvesting antenna to enhance the signal transduction of nucleic acid detection. Specifically, amphiphilic DNA-grafted FCPs are synthesized and self-assemble into FCP-SNA structures. Tuning the hydrophobicity of the graft copolymer can adjust the size and light-harvesting capability of the FCP-SNAs. We observe that more efficient signal amplification occurs in larger FCP-SNAs, as more chromophores are involved, and the energy transfer can go beyond the Förster radius. Accordingly, the optimized FCP-SNA shows an antenna effect of up to 37-fold signal amplification and the limit of detection down to 1.7 pM in microRNA detection. Consequently, the FCP-SNA is applied to amplified in situ nucleic acid detecting and imaging at the single-cell level.

Side-Chain-Tuned Molecular Packing Allows Concurrently Boosted Photoacoustic Imaging and NIR-II Fluorescence.

It is generally considered that photoacoustic imaging (PAI) and fluorescence imaging (FLI) cannot be enhanced concurrently, as they are dependent on competitive photophysical processes at the single-molecule level. Herein, we reveal that BDTR9-OC8 and BDTR9-C8, which have identical π-conjugated backbones but are substituted by side chains of different rigidity, show distinct phototheranostic properties in the aggregated state. The NIR-II FLI and PAI brightness of BDTR9-C8 nanoparticles are enhanced by 4.6 and 1.4 times compared with BDTR9-OC8 nanoparticles. Theoretical calculations and GIWAXS analysis revealed that BDTR9-C8 with rigid side chains shows a relative amorphous condensed state, which will benefit the efficient transportation of photo-generated excitons and phonons, subsequently enhancing the FLI and PAI signals. Besides, both nanoparticles exhibit excellent photothermal conversion efficiency due to their strong light-harvesting capability and are considered effective photothermal therapy materials. This work provides an illuminating strategy for material design in the future.

Hierarchical Chiral Supramolecular Nanoarchitectonics with Molecular Detection: Helical Structure Controls upon Self-Assembly and Coassembly.

The morphological transformation from microspheres to helical supramolecular nanofibers with controllable handedness is achieved by the introduction of molecular chirality based on amino acid derivatives (TDAP), and the chirality of the supramolecular architectures that are achieved is nullified through the coassembly of the equivalent TDAP enantiomers. The molecular detection of achiral melamine based on the R-TDAP-COOH supramolecular system is achieved by the appearance of helicity and inversion.

Advanced Cancer Starvation Therapy by Simultaneous Deprivation of Lactate and Glucose Using a MOF Nanoplatform.

Recent investigations reveal that lactate is not a waste product but a major energy source for cells, especially in the mitochondria, which can support cellular survival under glucose shortage. Accordingly, the new understanding of lactate prompts to target it together with glucose to pursue a more efficient cancer starvation therapy. Herein, zeolitic imidazolate framework-8 (ZIF-8) nanoplatforms are used to co-deliver α-cyano-4-hydroxycinnamate (CHC) and glucose oxidase (GOx) and fulfill the task of simultaneous depriving of lactate and glucose, resulting in a new nanomedicine CHC/GOx@ZIF-8. The synthesis conditions are carefully optimized in order to yield monodisperse and uniform nanomedicines, which will ensure reliable and steady therapeutic properties. Compared with the strategies aiming at a single carbon source, improved starvation therapy efficacy is observed. Besides, more than boosting the energy shortage, CHC/GOx@ZIF-8 can block the lactate-fueled respiration and relieve solid tumor hypoxia, which will enhance GOx catalysis activity, depleting extra glucose, and producing more cytotoxic H2 O2 . By the synergistically enhanced anti-tumor effect, both in vitro and in vivo cancer-killing efficacies of CHC/GOx@ZIF-8 show twice enhancements than the GOx mediated therapy. The results demonstrate that the dual-depriving of lactate and glucose is a more advanced strategy for strengthening cancer starvation therapy.

Mn-DNA coordination of nanoparticles for efficient chemodynamic therapy.

A kind of nanoparticle is developed for highly efficient chemodynamic therapy that only relies on the endogenous H2O2 of cancer cells. For this nanoparticle, high-molecular-weight DNA is used as the biocompatible carrier to load abundant Mn2+ ions. Therefore, the resultant Mn-DNA coordination nanoparticles can efficiently deliver and sensitively release Mn2+ in cancer cells, resulting in high toxicity through the Fenton-like reaction.

Genetically Encoded and Biologically Produced All-DNA Nanomedicine Based on One-Pot Assembly of DNA Dendrimers for Targeted Gene Regulation.

All-DNA nanomedicines have emerged as potential anti-tumor drugs. DNA nanotechnology provides all-DNA nanomedicines with unlimited possibilities in controlling the diversification of size, shape, and loads of the therapeutic motifs. As DNA is a biological polymer, it is possible to genetically encode and produce the all-DNA nanomedicines in living bacteria. Herein, DNA-dendrimer-based nanomedicines are designed to adapt to the biological production, which is constructed by the flexible 3-arm building blocks to enable a highly efficient one-pot DNA assembly. For the first time, a DNA nanomedicine, D4-3-As-DzSur, is successfully genetically encoded, biotechnologically produced, and directly self-assembled. The performance of the biologically produced D4-3-As-DzSur in targeted gene regulation has been confirmed by in vitro and in vivo studies. The biological production capability will fulfill the low-cost and large-scale production of all-DNA nanomedicines and promote clinical applications.

An NIR-II-Emissive Photosensitizer for Hypoxia-Tolerant Photodynamic Theranostics.

As a common feature in a majority of malignant tumors, hypoxia has become the Achilles' heel of photodynamic therapy (PDT). The development of type-I photosensitizers that show hypoxia-tolerant PDT efficiency provides a straightforward way to address this issue. However, type-I PDT materials have rarely been discovered. Herein, a π-conjugated molecule with A-D-A configuration, COi6-4Cl, is reported. The H2 O-dispersible nanoparticle of COi6-4Cl can be activated by an 880 nm laser, and displays hypoxia-tolerant type I/II combined PDT capability, and more notably, a high NIR-II fluorescence with a quantum yield over 5%. Moreover, COi6-4Cl shows a negligible photothermal conversion effect. The non-radiative decay of COi6-4Cl is suppressed in the dispersed and aggregated state due to the restricted molecular vibrations and distinct intermolecular steric hindrance induced by its four bulky side chains. These features make COi6-4Cl a distinguished single-NIR-wavelength-activated phototheranostic material, which performs well in NIR-II fluorescence-guided PDT treatment and shows an enhanced in vivo anti-tumor efficiency over the clinically approved Chlorin e6, by the equal stresses on hypoxia-tolerant anti-tumor therapy and deep-penetration imaging. Therefore, the great potential of COi6-4Cl in precise PDT cancer therapy against hypoxia challenges is demonstrated.