Liposomes co-loaded with metformin and chlorin e6 modulate tumor hypoxia during enhanced photodynamic therapy

Though photodynamic therapy (PDT) has been widely used in the non-invasive destruction of solid tumors,the therapeutic efficacy of PDT is often limited by the hypoxic tumor environment.Herein,we report the innovative use of metformin,an oral hypoglycemic agent commonly used in the treatment of type Ⅱ diabetes,to improve tumor oxygenation,and overcome tumor hypoxia-associated resistance to PDT.In our design,hydrophilic metformin and modified hydrophobic chlorin e6 (HCe6) are co-encapsulated within the inner cavity and outer membrane of liposomes,respectively.Due to the high uptake of liposome nanoparticles by tumors,and the sustained release of metformin,the intravenous administration of metformin (Met)-HCe6-Liposome nanoparticles greatly improves tumor oxygenation in several different tumor models,as revealed by in vivo photoacoustic imaging and ex vivo immunofluorescence staining.Systemic administration of Met-HCe6-Liposomes followed by in vivo PDT achieved significantly improved therapeutic effects compared to that of PDT without metformin.Hence,our study represents a new strategy for the improvement of PDT efficacy through the modulation of tumor oxygenation by clinically approved agents.     

Gold nanorod-photosensitizer conjugate with extracellular pH-driven tumor targeting ability for photothermal/photodynamic therapy

Chlorin e6-pHLIPss-AuNRs, a gold nanorod-photosensitizer conjugate containing a pH （low） insertion peptide （pHLIP） with a disulfide bond which imparts extracellular pH （pHe）-driven tumor targeting ability, has been successfully developed for bimodal photodynamic and photothermal therapy. In this bimodal therapy, chlorin e6 （Ce6）, a second-generation photosensitizer （PS）, is used for photodynamic therapy （PDT）. Gold nanorods （AuNRs） are used as a hyperthermia agent for photothermal therapy （PTT） and also as a nanocarrier and quencher of Ce6. pHLIPss is designed as a pile-driven targeting probe to enhance accumulation of Ce6 and AuNRs in cancer cells at low pH. In Ce6- pHLIPss-AuNRs, Ce6 is close to and quenched by AuNRs, causing little PDT effect. When exposed to normal physiological pH 7.4, Ce6-pHLIPs~-AuNRs loosely associate with the cell membrane. However, once exposed to acidic pH 6.2, pHLIP actively inserts into the cell membrane, and the conjugates are translocated into cells. When this occurs, Ce6 separates from the AuNRs as a result of disulfide bond cleavage caused by intracellular glutathione （GSH）, and singlet oxygen is produced for PDT upon light irradiation. In addition, as individual PTT agent, AuNRs can enhance the accumulation of PSs in the tumor by the enhanced permeation and retention （EPR） effect. Therefore, as indicated by our data, when exposed to acidic pH, Ce6-pHLIPss-AuNRs can achieve synergistic PTT/PDT bimodality for cancer treatment.     

Aza-BODIPY-based phototheranostic nanoagent for tissue oxygen auto-adaptive photodynamic/photothermal complementary therapy

Tumor oxygen spatial heterogeneity is a critical challenge for the photodynamic inhibition of solid tumors.Development of an intelligent nanoagent to initiate optimal therapeutics according to the localized oxygen levels is an effective settlement.Herein,we report an activatable nanoagent(BDP-Oxide nanoparticles(NPs))to enable the oxygen auto-adaptive photodynamic/photothermal complementaly treatment.Upon the nanoagent accumulated in the tumor region,the low extracellular pH could trigger the disassociation of the nanoagent to release the phototheranostic agent,BDP-Oxide,which will subsequently afford the fluorescence imaging-guided photodynamic oxidation after it gets into the outer oxygen-rich tumors.Along with the penetration deepening in the solid tumor,furthermore,BDP-Oxide could be reduced into BDP by the cytochrome P450(CYP450)enzymes activated in the low oxygen tension regions of inner hypoxic tumors,which will switch on the photothermal and photoacoustic effects.Overall,the BDP-Oxide NPs-enabled photodynamic/photothermal complementary therapy significantly suppressed the solid tumor growth(inhibition rate of 94.8%).This work proposes an intelligent platform to address the oxygen partial pressure for the optimization of cancer phototherapeutics.     

Cyanobacteria-based near-infrared light-excited self-supplying oxygen system for enhanced photodynamic therapy of hypoxic tumors

Tumor hypoxia has been considered to induce tumor cell resistance to radiotherapy and anticancer chemotherapy,as well as predisposing for increased tumor metastases.Therefore,strategies for the eradication of the hypoxic tumor are highly desirable.Photodynamic therapy(PDT)is a new technique that can be used to treat tumors using laser irradiation to photochemically activate a photosensitizer.Compared to traditional radiotherapy and chemotherapy,photodynamic therapy has many advantages,such as good selectivity,low toxicity,and less trauma and resistance.However,PDT is oxygen-dependent,and the lack of oxygen in hypoxic tumors renders photodynamic therapy ineffective.Cyanobacteria,the earliest photosynthetic oxygen-generating organisms,can utilize water as an electron donor to reduce CO₂ into organic carbon compounds along with continuously releasing oxygen under sunlight.Inspired by this,herein,cyanobacteria were used as a living carrier of photosensitizer conjugated upconversion nanoparticles(UCNP)to construct a self-supplying oxygen PDT system.Improvement in the PDT efficiency for hypoxic tumors can be achieved as a result of in situ oxygen production by cyanobacteria under near-infrared(NIR)light using UCNP as a light harvesting antenna.A successful demonstration of this concept would be of great significance and could open the door to a new generation of carrier systems in the field of hypoxia-targeted drug transport platforms.     

Fucoidan-Based Theranostic Nanogel for Enhancing Imaging and Photodynamic Therapy of Cancer

In this study, a fucoidan-based theranostic nanogel(CFN-gel) consisting of a fucoidan backbone, redox-responsive cleavable linker and photosensitizer is developed to achieve acti-vatable near-infrared fluorescence imaging of tumor sites and an enhanced photodynamic therapy(PDT) to induce the com-plete death of cancer cells. A CFN-gel has nanomolar a nity for P-selectin, which is overexpressed on the surface of tumor neovascular endothelial cells as well as many other cancer cells. Therefore, a CFN-gel can enhance tumor accumulation through P-selectin targeting and the enhanced permeation and retention e ect. Moreover, a CFN-gel is non-fluorescent and non-phototoxic upon its systemic administration due to the aggregation-induced self-quenching in its fluorescence and singlet oxygen generation. After internalization into cancer cells and tumor neovascular endothelial cells, its photoactivity is recovered in response to the intracellular redox potential, thereby enabling selective near-infrared fluorescence imaging and an enhanced PDT of tumors. Since a CFN-gel also shows nanomolar a nity for the vascular endothelial growth factor, it also provides a significant anti-tumor e ect in the absence of light treatment in vivo. Our study indicates that a fucoidan-based theranostic nanogel is a new theranostic material for imaging and treating cancer with high e cacy and specificity.     

Deep-Tissue Photothermal Therapy Using Laser Illumination at NIR-Ⅱa Window

Photothermal therapy(PTT)using near-infrared(NIR)light for tumor treatment has triggered extensive attentions because of its advantages of noninvasion and convenience.The current research on PTT usually uses lasers in the first NIR window(NIR-I;700–900 nm)as irradiation source.However,the second NIR window(NIR-II;1000–1700 nm)especially NIRIIa window(1300–1400 nm)is considered much more promising in diagnosis and treatment as its superiority in penetration depth and maximum permissible exposure over NIR-I window.Hereby,we propose the use of laser excitation at 1275 nm,which is approved by Food and Drug Administration for physical therapy,as an attractive technique for PTT to balance of tissue absorption and scattering with water absorption.Specifically,CuS-PEG nanoparticles with similar absorption values at 1275 and 808 nm,a conventional NIR-I window for PTT,were synthesized as PTT agents and a comparison platform,to explore the potential of 1275 and 808 nm lasers for PTT,especially in deep-tissue settings.The results showed that 1275 nm laser was practicable in PTT.It exhibited much more desirable outcomes in cell ablation in vitro and deep-tissue antitumor capabilities in vivo compared to that of 808 nm laser.NIR-IIa laser illumination is superior to NIR-I laser for deep-tissue PTT,and shows high potential to improve the PTT outcome.     

Multifunctional core/satellite polydopamine@Nd<Superscript>3+</Superscript>-sensitized upconversion nanocomposite: A single 808 nm near-infrared light-triggered theranostic platform for <Emphasis Type="Italic">in vivo</Emphasis> imaging-guided photothermal therapy

Significant attenuation and overheating,caused by the absorption of the excitation band (980 nm) in water,are the major obstacles in the in vivo application of lanthanide-doped upconversion nanopartides (UCNPs).Therefore,appropriately-structured Nd3+-doped UCNPs with 808 nm excitation could be a promising alternative.Herein,we developed core-shell-shell structured Nd3+-sensitized UCNPs as imaging agents,and decorated them onto the surface of polydopamine (PDA) to construct a novel multifunctional core/satellite nanotheranostic (PDA@UCNPs) for in vivo imaging guidance photothermal therapy using single 808 nm laser irradiation.The core-shell-shell structured design enabled outstanding upconversion luminescence properties and strong X-ray attenuation,thereby making the nanocomposites potential candidates for excellent upconversion luminescence/computed tomography dual modal imaging.In addition,the PDA core not only provides high photothermal conversion efficiency and outstanding antitumor effect,but also endows the platform with robust biocompatibility owing to its natural features.Therefore,this multifunctional nanocomposite could be a promising theranostic in future oncotherapy,with high therapeutic effectiveness but low side effects.This study would stimulate interest in designing bioapplication-compatible multifunctional nanocomposites,especially for cancer diagnosis and treatment in vivo.     

Fabrication of multifunctional polydopamine-coated gold nanobones for PA/CT imaging and enhanced synergistic chemo-photothermal therapy

Multimodal imaging-guided chemo-photothermal therapy is an excellent cancer treatment,which can not only efficiently against tumor,but also can offer precise treatment window and real-time monitoring of the treatment efficiency.In our work,polydopamine(PDA)-coated gold nanobones(AuNBs@PDA nanocomplexes)were designed for this approach.The AuNBs@PDA nanocomplexes have strong absorbance in the near infrared(NIR)region and higher photothermal conversion efficiency(75.48%)than gold nanobones alone,which was facilitated for photoacoustic imaging and photothermal therapy.Besides,the loading efficiency of doxorubicin(DOX)by AuNBs@PDA nanocomplexes could be up to about 70%and DOX release from AuNBs@PDA/DOX nanocomplexes sensitively response to the lower pH environment and NIR laser irradiation,which makes them become the excellent nano-carrier for the delivery of chemotherapy drug.In vitro and in vivo studies showed significant cytotoxicity and antitumor efficacy by the AuNBs@PDA/DOX nanoplatform with negligible side effects.Meanwhile,the nanoplatform was also successfully employed for computed tomography(CT)imaging,attributing to the high atomic number and high X-ray attenuation coefficient of gold.Therefore,we believed that the proposed PDA-coated gold nanobones would be a novel multifunctional theranostic nanoagent to realize the PA/CT imaging-guided chemo-photothermal therapy of cancer.     

Black phosphorus quantum dots as multifunctional nanozymes for tumor photothermal/catalytic synergistic therapy

Nanozymes are nanomaterials with enzyme-like properties that have attracted significant interest owing to their high stability,easy preparation,and tunable catalytic properties,especially in the field of cancer therapy.However,the unfavorable catalytic effects of nanozymes in the acidic tumor microenvironment have limited their applications.Herein,we developed a biomimetic erythrocyte membrane-camouflaged ultrasmall black phosphorus quantum dots(BPQDs)nanozymes that simultaneously exhibited an exceptional near-infrared(NIR)photothermal property and dramatically photothermal-enhanced glucose oxidase(GOx)-like activity in the acidic tumor microenvironment.We demonstrated the engineered BPQDs gave a photothermal conversion efficiency of 28.9%that could rapidly heat the tumor up to 50℃ while effectively localized into tumors via homing peptide iRGD leading after intravenously injection.Meanwhile,the significantly enhanced GOx-like activity of BPQDs under NIR irradiation was capable of catalytical generating massive toxic reactive oxygen species via using cellular glucose.By combining the intrinsic photothermal property and the unique photothermal-enhanced GOx-like catalytic activity,the developed BPQDs were demonstrated to be an effective therapeutic strategy for inhibiting tumor growth in vivo.We believe that this work will provide a novel perspective for the development of nanozymes in tumor catalytic therapy.     

Interface evolution in the platelet-like SiC@C and SiC@SiO<Subscript>2</Subscript> monocrystal nanocapsules

Carbon-coated SiC@C nanocapsules (NCs) with a hexagonal platelet-like morphology were fabricated by a simple direct current (DC) arc-discharge plasma method.The SiC@C NCs were monocrystalline,120-150 nm in size,and approximately 50 nm thick.The formation of the as-prepared SiC@C NCs included nucleation of truncated octahedral SiC seeds and subsequent anisotropic growth of the seeds into hexagonal nanoplatelets in a carbon-rich atmosphere.The disordered carbon layers on the SiC@C NCs were converted into SiO2 shells of SiC@SiO2 NCs by heat treatment at 650 ℃ in air,during which the shape and inherent characteristics of the crystalline SiC core were obtained.The interface evolution from carbon to SiO2 shells endowed the SiC@SiO2 NCs with enhanced photocatalytic activity due to the hydrophilic and transparent nature of the SiO2 shell,as well as to the photosensitive SiC nanocrystals.The band gap of the nanostructured SiC core was determined to be 2.70 eV.The SiC@SiO2 NCs degraded approximately 95％ of methylene blue in 160 min under visible light irradiation.     

Multifunctional oxygen-enriching nano-theranostics for cancer-specific magnetic resonance imaging and enhanced photodynamic/photothermal therapy

The combination of photodynamic therapy (PDT) and photothermal therapy (PTT) has attracted much interest in recent years, but non-specific distribution of photosensitizers and intrinsic tumor hypoxic microenvironment have continued to limit its therapeutic efficiency. We herein report a nano-theranostic system, denoted as Ce6-CuS/MSN@PDA@MnO₂-FA NPs, which combines PDT, PTT, magnetic resonance (MR) imaging with hypoxia-relieving and tumor-targeting functionalities. Central to this design is the use of mussel-inspired polydopamine (PDA) coating to encapsulate the chlorin e6 (Ce6) and copper sulfide nanoparticles (CuS NPs) loaded mesoporous silica nanoparticle (MSN) core. The PDA coating not only acts as pH sensitive gatekeeper to prevent the premature release of Ce6 under non-acidic tumor microenvironment (TME), but also facilitates post-functionalization so that hypoxia-relieving MnO₂ nano-sheets and tumor-targeting ligand folic acid-PEG-thiol (FA-PEG-SH) can be decorated on the outer part of the drug system. In vitro and in vivo measurements clearly demonstrated that all these functionalities worked synergistically as expected. The system, having a low dark cytotoxicity, can be effectively internalized by 4T1 cells and decrease the cell viability to 2% upon 660 nm/808 nm laser irradiation. Tumors in 4T1 tumor-bearing mice can almost be completely destroyed in 2 weeks via combined PDT/PTT. Together with the TME-sensitive MR imaging performance demonstrated, Ce6-CuS/MSN@PDA@MnO₂-FA NPs represent a multifunctional prototype which holds great potential to be developed into clinical theranostics.

     

Six Birds with One Stone: Versatile Nanoporphyrin for Single-Laser-Triggered Synergistic Phototheranostics and Robust Immune Activation

Simultaneous photodynamic therapy (PDT) and photothermal therapy (PTT) can reduce the risks of drug leakage, body burden, and preparation complexity in traditional combination PDT/PTT. Here, a versatile nanoporphyrin (Pp18-lipos) self-assembled from lipid–purpurin 18 conjugates (Pp18-lipids) and pure lipids is presented. The as-prepared Pp18-lipos with 2 mol% Pp18-lipids can perform effective PDT and fluorescence imaging. The Pp18-lipos with 65 mol% Pp18 can perform potent PTT and photoacoustic imaging. The chelation of Mn²⁺ endows the Pp18-lipids-Mn²⁺ a high T₁-weighted magnetic resonance imaging contrast. Notably, pretreatment of low-dose PDT facilitates the endocytosis and tumor accumulation of Pp18-lipos, thus achieving synergistic PDT/PTT. Upon exposure to a single 705 nm-laser, the combination of PDT/PTT achieves a significantly higher tumor growth inhibition rate than PDT or PTT alone. In addition, it is found that the synergistic PDT/PTT triggers more potent anti-tumor immune response including tumor infiltration of immune cells and release of related cytokines.     

Photosensitizer‐Conjugated Albumin−Polypyrrole Nanoparticles for Imaging‐Guided In Vivo Photodynamic/Photothermal Therapy

Conjugated polymers with strong absorbance in the near‐infrared (NIR) region have been widely explored as photothermal therapy agents due to their excellent photostability and high photothermal conversion efficiency. Herein, polypyrrole (PPy) nanoparticles are fabricated by using bovine serum albumin (BSA) as the stabilizing agent, which if preconjugated with photosensitizer chlorin e6 (Ce6) could offer additional functionalities in both imaging and therapy. The obtained PPy@BSA‐Ce6 nanoparticles exhibit little dark toxicity to cells, and are able to trigger both photodynamic therapy (PDT) and photothermal therapy (PTT). As a fluorescent molecule that in the meantime could form chelate complex with Gd³⁺, Ce6 in PPy@BSA‐Ce6 nanoparticles after being labeled with Gd³⁺ enables dual‐modal fluorescence and magnetic resonance (MR) imaging, which illustrate strong tumor uptake of those nanoparticles after intravenous injection into tumor‐bearing mice. In vivo combined PDT and PTT treatment is then carried out after systemic administration of PPy@BSA‐Ce6, achieving a remarkably improved synergistic therapeutic effect compared to PDT or PTT alone. Hence, a rather simple one‐step approach to fabricate multifunctional nanoparticles based on conjugated polymers, which appear to be promising in cancer imaging and combination therapy, is presented.     

<Emphasis Type="Italic">In situ</Emphasis> synthesis of graphene oxide/gold nanorods theranostic hybrids for efficient tumor computed tomography imaging and photothermal therapy

Graphene oxide/gold nanorod (GO/GNR) nanohybrids were synthesized with a GO- and gold-seed-mediated in situ growth method at room temperature by mixing polystyrene sulfonate (PSS) functionalized GO, secondary growth solution, and gold seeds. Compared with ex situ preparation methods of GO/GNRs or graphene (G)/GNRs, the in situ synthesis of GO/GNRs addressed the issue of the aggregation of the GNRs before their attachment onto the GO. The method is straightforward and environment-friendly. The GO/GNRs showed a remarkable photothermal effect in vitro. The temperature of the GO/GNR nanohybrids increased from 25 to 49.9 °C at a concentration of 50 μg/mL after irradiation with an 808-nm laser (0.4 W/cm²) for 6 min. Additionally, the GO/GNRs exhibited good optical and morphological stability and photothermal properties after six cycles of laser irradiation. Upon injection of the GO/GNRs into xenograft tumors, excellent computed tomography (CT) imaging properties and photothermal effect were obtained. The preclinical CT agent iohexol was combined with the GO/GNRs and further enhanced CT imaging. Therefore, the GO/GNR nanohybrids have great potential for precise CT-image-guided tumor photothermal treatment.

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Photothermal therapy by using titanium oxide nanoparticles

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.

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First Demonstration of Gold Nanorods‐Mediated Photodynamic Therapeutic Destruction of Tumors via Near Infra‐Red Light Activation

Previously, a large volume of papers reports that gold nanorods (Au NRs) are able to effectively kill cancer cells upon high laser doses (usually 808 nm, 1–48 W/cm²) irradiation, leading to hyperthermia‐induced destruction of cancer cells, i.e, photothermal therapy (PTT) effects. Combination of Au NRs‐mediated PTT and organic photosensitizers‐mediated photodynamic therapy (PDT) were also reported to achieve synergistic PTT and PDT effects on killing cancer cells. Herein, we demonstrate for the first time that Au NRs alone can sensitize formation of singlet oxygen (¹O₂) and exert dramatic PDT effects on complete destrcution of tumors in mice under very low LED/laser doses of single photon NIR (915 nm, <130 mW/cm²) light excitation. By changing the NIR light excitation wavelengths, Au NRs‐mediated phototherapeutic effects can be switched from PDT to PTT or combination of both. Both PDT and PTT effects were confirmed by measurements of reactive oxygen species (ROS) and heat shock protein (HSP 70), singlet oxygen sensor green (SOSG) sensing, and sodium azide quenching in cellular experiments. In vivo mice experiments further show that the PDT effect via irradiation of Au NRs by 915 nm can destruct the B16F0 melanoma tumor in mice far more effectively than doxorubicin (a clinically used anti‐cancer drug) as well as the PTT effect (via irradiation of Au NRs by 780 nm light). In addition, we show that Au NRs can emit single photon‐induced fluorescence to illustrate their in vivo locations/distribution.     

Integration of IR‐808 Sensitized Upconversion Nanostructure and MoS2 Nanosheet for 808 nm NIR Light Triggered Phototherapy and Bioimaging

Near infrared (NIR) light triggered phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT) affords superior outcome in cancer treatment. However, the reactive oxygen species (ROS) generated by NIR‐excited upconversion nanostructure is limited by the feeble upconverted light which cannot activate PDT agents efficiently. Here, an IR‐808 dye sensitized upconversion nanoparticle (UCNP) with a chlorin e6 (Ce6)‐functionalized silica layer is developed for PDT agent. The two booster effectors (dye‐sensitization and core–shell enhancement) synergistically amplify the upconversion efficiency, therefore achieving superbright visible emission under low 808 nm light excitation. The markedly amplified red light subsequently triggers the photosensitizer (Ce6) to produce large amount of ROS for efficient PDT. After the silica is endowed with positive surface, these PDT nanoparticles can be easily grafted on MoS₂ nanosheet. As the optimal laser wavelength of UCNPs is consistent with that of MoS₂ nanosheet for PTT, the invented nanoplatform generates both abundant ROS and local hyperthermia upon a single 808 nm laser irradiation. Both the in vitro and in vivo assays validate that the innovated nanostructure presents excellent cancer cell inhibition effectiveness by taking advantages of the synergistic PTT and PDT, simultaneously, posing trimodal (upconversion luminescence/computed tomography (CT)/magnetic resonance imaging (MRI) imaging capability.     

Achieving High‐Performance Photothermal and Photodynamic Effects upon Combining D–A Structure and Nonplanar Conformation

Various organic nanoagents have been developed for photothermal therapy (PTT) and photodynamic therapy (PDT) under near‐infrared (NIR) irradiation. Among them, small molecule‐based nanoagents are very attractive due to their advantages of well‐defined chemical structures, high purity, good reproducibility, and easy processability. However, only a few small molecule‐based nanoagents have been developed for PDT under NIR irradiation. Moreover, the mechanism of PDT under NIR is still elusive. Herein, a semiconducting small molecule (BTA) with donor–acceptor–donor structure and twisted conformation is developed for PDT/PTT under NIR irradiation. A large π‐conjugated electron‐deficient unit is used as the core to couple with two electron‐donating units, ensuring the strong absorption under 808 nm. Moreover, the donor–acceptor structures and twisted conformation can reduce the energy gap between the singlet and triplet states (?E_ST) to afford effective intersystem crossing, beneficial for reactive oxygen species generation. The mechanism is probed by experimental and theoretical evidence. Moreover, the BTA nanoparticles exhibit excellent biocompatibility and PTT/PDT in vitro performance under NIR irradiation. This provides a strategy for designing highly efficient PDT/PTT molecular materials.     

Dendritic Plasmonic CuPt Alloys for Closed-Loop Multimode Cancer Therapy with Remarkably Enhanced Efficacy

The outcome of laser-triggered plasmons-induced phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is significantly limited by the hypoxic tumor microenvironment and the upregulation of heat shock proteins (HSPs) in response to heat stress. Mitochondria, the biological battery of cells, can serve as an important breakthrough to overcome these obstacles. Herein, dendritic triangular pyramidal plasmonic CuPt alloys loaded with heat-sensitive NO donor N, N′-di-sec-butyl-N, N′-dinitroso-1,4-phenylenediamine (BNN) is developed. Under 808 nm laser irradiation, plasmonic CuPt can generate superoxide anion free radicals (·O₂⁻) and heat simultaneously. The heat generated can then trigger the release of NO gas, which not only enables gas therapy but also damages the mitochondrial respiratory chain. Impaired mitochondrial respiration leads to reduced oxygen consumption and insufficient intracellular ATP supply, which effectively alleviates tumor hypoxia and undermines the synthesis of HSPs, in turn boosting plasmonic CuPt-based PDT and mild PTT. Additionally, the generated NO and ·O₂⁻ can react to form more cytotoxic peroxynitrite (ONOO⁻). This work describes a plasmonic CuPt@BNN (CPB) triggered closed-loop NO gas, free radicals, and mild photothermal therapy strategy that is highly effective at reciprocally promoting antitumor outcomes.