Hydroxyl‐Rich Polycation Brushed Multifunctional Rare‐Earth‐Gold Core–Shell Nanorods for Versatile Therapy Platforms

It is of great significance to develop a multifunctional imaging‐guided therapeutic platform with ideal resolution and sensitivity. Notably, rare‐earth (RE) nanoparticles are attractive candidates for multimodal imaging due to their unique optical and magnetic properties. In this work, a rational design of hierarchical nanohybrids employing RE‐Au hetero‐nanostructures is proposed. 1D RE nanorods are adopted as the core to facilitate cellular internalization with the coating of gold nanoshells for photothermal performances. Hydroxyl‐rich polycations with low cytotoxicity are grafted onto the surface of RE‐Au to produce RE‐Au‐PGEA (ethanolamine‐functionalized poly(glycidyl methacrylate)) nanohybrids with impressive gene transfection capability. Given the virtues of all the components, the feasibility of RE‐Au‐PGEA for multifunctional photoacoustic, computed tomography, magnetic resonance, upconversion luminescence imaging, and complementary photothermal therapy/gene therapy therapy is investigated in detail in vitro and in vivo. The visualization of the therapeutic processes with comprehensive information renders RE‐Au‐PGEA nanohybrid an intriguing platform to realize enhanced antitumor efficiency.     

Core–Satellite Mesoporous Silica–Gold Nanotheranostics for Biological Stimuli Triggered Multimodal Cancer Therapy

A core–satellite nanotheranostic agent with pH‐dependent photothermal properties, pH‐triggered drug release, and H₂O₂‐induced catalytic generation of radical medicine is fabricated to give a selective and effective tumor medicine with three modes of action. The nanocomplex (core–satellite mesoporous silica–gold nanocomposite) consists of amino‐group‐functionalized mesoporous silica nanoparticles (MSN‐NH₂) linked to L‐cysteine‐derivatized gold nanoparticles (AuNPs‐Cys) with bridging ferrous iron (Fe²⁺) ions. The AuNPs‐Cys serve as both removable caps that control drug release (doxorubicin) and stimuli‐responsive agents for selective photothermal therapy. Drug release and photothermal therapy are initiated by the cleavage of Fe²⁺ coordination bonds at low pH and the spontaneous aggregation of the dissociated AuNPs‐Cys. In addition, the Fe²⁺ is able to catalyze the decomposition of hydrogen peroxide abundant in cancer cells by a Fenton‐like reaction to generate high‐concentration hydroxyl radicals (·OH), which then causes cell damage. This system requires two tumor microenvironment conditions (low pH and considerable amounts of H₂O₂) to trigger the three therapeutic actions. In vivo data from mouse models show that a tumor can be completely inhibited after two weeks of treatment with the combined chemo‐photothermal method; the data directly demonstrate the efficiency of the MSN–Fe–AuNPs for tumor therapy.     

One‐Pot Synthesis of Dual Stimulus‐Responsive Degradable Hollow Hybrid Nanoparticles for Image‐Guided Trimodal Therapy

Exploiting exogenous and endogenous stimulus‐responsive degradable nanoparticles as drug carriers can improve drug delivery systems (DDSs). The use of hollow nanoparticles may facilitate degradation, and combination of DDS with photodynamic therapy (PDT) and photothermal therapy (PTT) may enhance the anticancer effects of treatments. Here, a one‐pot synthetic method is presented for an anticancer drug (doxorubicin [DOX]) and photosensitizer‐containing hollow hybrid nanoparticles (HNPs) with a disulfide and siloxane framework formed in response to exogenous (light) and endogenous (intracellular glutathione [GSH]) stimuli. The hollow HNPs emit fluorescence within the near‐infrared window and allow for the detection of tumors in vivo by fluorescence imaging. Furthermore, the disulfides within the HNP framework are cleaved by intracellular GSH, deforming the HNPs. Light irradiation facilitates penetration of GSH into the HNP framework and leads to the collapse of the HNPs. As a result, DOX is released from the hollow HNPs. Additionally, the hollow HNPs generate singlet oxygen (¹O₂) and heat in response to light; thus, fluorescence imaging of tumors combined with trimodal therapy consisting of DDS, PDT, and PTT is feasible, resulting in superior therapeutic efficacy. Thus, this method may have several applications in imaging and therapeutics in the future.     

Hierarchical Nanohybrids of Gold Nanorods and PGMA‐Based Polycations for Multifunctional Theranostics

Organic/inorganic nanohybrids hold great importance in fabricating multifunctional theranostics to integrate therapeutic functions with real‐time imaging. Although Au nanorods (NRs) have been employed for theranostics, complicated design of materials limits their practical applications. In this work, new multifunctional theranostic agents are designed and synthesized employing Au NRs with desirable near‐infrared absorbance as the cores. A facile “grafting‐onto” approach is put forward to prepare the series of hierarchical nanohybrids (Au‐PGEA and Au‐PGED) of Au NRs and poly(glycidyl methacrylate)‐based polycations. The resultant nanohybrids can be utilized as gene carriers with high gene transfection performances. The structural effect of polycations on gene transfection is investigated in detail, and Au‐PGEA with abundant hydroxyl groups on the surface exhibits superior performance. Au‐PGEA nanohybrids are further validated to possess remarkable capability of combined photothermal therapy (PTT) and gene therapy (GT) for complementary tumor treatment. Moreover, significantly enhanced computed tomography (CT)/photoacoustic (PA) signals are detected both in vitro and in vivo, verifying the potential of Au‐PGEA for dual‐modal imaging with precise and accurate information. Therefore, these multifunctional nanohybrids fabricated from a simple and straightforward strategy are promising for in vivo dual‐modal CT/PA imaging guided GT/PTT therapy with high antitumor efficacy.     

Magnetic (Hyper)Thermia or Photothermia? Progressive Comparison of Iron Oxide and Gold Nanoparticles Heating in Water,in Cells,and In Vivo

Magnetic hyperthermia (MHT) and photothermal therapy (PTT) are emergent state‐of‐the‐art modalities for thermal treatment of cancer. While their mechanisms of action have distinct physical bases, both approaches rely on nanoparticle‐mediated remote onset of thermotherapy. Yet, are the two heating techniques interchangeable? Here, the heating obtained either with MHT or with PTT is compared. The heating is assessed in distinct environments and involves a set of nanomaterials differing in shape (spheres, cubes, stars, shells, and rods) as well as in composition (maghemite, magnetite, cobalt ferrite, and gold). The nanoparticle's heating efficacy in an aqueous medium is first evaluated. Subsequently, the heating efficiency within the cellular environment, where intracellular processing markedly decreases MHT, is compared. Conversely, endosomal sequestration could have a positive effect on PTT. Finally, iron oxide nanocubes and gold nanostars are compared in MHT and PTT in vivo within the heterogeneous intratumoral environment. Overall, two distinct therapeutic approaches, related to high dosage allowing MHT and low dosage associated with PTT, are identified. It is also demonstrated that PTT mediated by magnetic nanoparticles has an efficacy that is comparable to that of plasmonic nanoparticles, but only at significant nanoparticle dosages. At low concentrations, only plasmonic nanoparticles can deliver a therapeutic heating.     

Synthesis,Functionalization, and Bioconjugation of Monodisperse,Silica‐Coated Gold Nanoparticles: Robust Bioprobes

Herein, we report an efficient process for preparing monodisperse Au@SiO₂ nanoparticles using homogeneous shaking and without the use of surface‐coupling silane agents or large stabilizers. The resulting pure‐silica surface of the Au@SiO₂ nanoparticles is very important for straightforward surface functionalization with different functional groups via well‐established silica surface chemistry. Subsequent covalent bioconjugation of the aldehyde‐functionalized Au@SiO₂ nanoparticles with various biomolecules is successfully employed to make robust nanoprobes for fast, colorimetric DNA and protein detection based on the sequence‐specific hybridization properties of DNA and the specific binding affinity between proteins, respectively.     

Self‐Mineralized Photothermal Bacteria Hybridizing with Mitochondria‐Targeted Metal–Organic Frameworks for Augmenting Photothermal Tumor Therapy

A photothermal bacterium (PTB) is reported for tumor‐targeted photothermal therapy (PTT) by using facultative anaerobic bacterium Shewanella oneidensis MR‐1 (S. oneidensis MR‐1) to biomineralize palladium nanoparticles (Pd NPs) on its surface without affecting bacterial activity. It is found that PTB possesses superior photothermal property in near infrared (NIR) regions, as well as preferential tumor‐targeting capacity. Zeolitic imidazole frameworks‐90 (ZIF‐90) encapsulating photosensitizer methylene blue (MB) are hybridized on the surface of living PTB to further enhance PTT efficacy. MB‐encapsulated ZIF‐90 (ZIF‐90/MB) can selectively release MB at mitochondria and cause mitochondrial dysfunction by producing singlet oxygen (¹O₂) under light illumination. Mitochondrial dysfunction further contributes to adenosine triphosphate (ATP) synthesis inhibition and heat shock proteins (HSPs) down‐regulated expression. The PTB‐based therapeutic platform of PTB@ZIF‐90/MB demonstrated here will find great potential to overcome the challenges of tumor targeting and tumor heat tolerance in PTT.     

Redox‐Responsive and Drug‐Embedded Silica Nanoparticles with Unique Self‐Destruction Features for Efficient Gene/Drug Codelivery

The development of advanced gene/drug codelivery carriers with stimuli‐responsive release manner for complementary cancer therapy is desirable. In this study, novel disulfide‐bridged and doxorubicin (DOX)‐embedded degradable silica nanoparticles (DS‐DOX) with unique self‐destruction features are synthesized by a facile one‐pot method. In order to realize codelivery of genes and drugs, the surface of DS‐DOX nanoparticles is readily functionalized with the assembled polycation (CD‐PGEA), comprising one β‐cyclodextrin core and two ethanolamine‐functionalized poly(glycidyl methacrylate) arms, to achieve DS‐DOX‐PGEA. The redox‐responsive self‐destruction behavior of DS‐DOX imparts DS‐DOX‐PGEA with a better ability to release anticancer drug DOX, while the low‐toxic hydroxyl‐rich CD‐PGEA brushes can efficiently deliver genes for cancer treatment. Very interestingly, the degradation process of DS‐DOX starts from the outside, while the destruction of the degradable silica (DS) nanoparticles without DOX begins from the center of the nanoparticles. The embedded DOX inside the DS‐DOX nanoparticles can significantly influence the structures and facilitate the cellular uptake and the subsequent gene transfection. The as‐developed DS‐DOX‐PGEA nanostructure with coordinating biodegradability, stimuli‐responsiveness, and controlled release manner might be desirable gene/drug codelivery carriers for clinical cancer treatment.     

An Acceptor–Donor–Acceptor Structured Small Molecule for Effective NIR Triggered Dual Phototherapy of Cancer

Dual phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is regarded as a more effective method for cancer treatment than single PDT or PTT. However, development of single component and near‐infrared (NIR) triggered agents for efficient dual phototherapy remains a challenge. Herein, a simple strategy to develop dual‐functional small‐molecules‐based photosensitizers for combined PDT and PTT treatment is proposed through: 1) finely modulating HOMO–LUMO energy levels to regulate the intersystem crossing (ISC) process for effective singlet oxygen (¹O₂) generation for PDT; 2) effectively inhibiting fluorescence via strong intramolecular charge transfer (ICT) to maximize the conversion of photo energy to heat for PTT or ISC process for PDT. An acceptor–donor–acceptor (A‐D‐A) structured small molecule (CPDT) is designed and synthesized. The biocompatible nanoparticles, FA‐CNPs, prepared by encapsulating CPDT directly with a folate functionalized amphipathic copolymer, present strong NIR absorption, robust photostability, cancer cell targeting, high photothermal conversion efficiency as well as efficient ¹O₂ generation under single 808 nm laser irradiation. Furthermore, synergistic PDT and PTT effects of FA‐CNPs in vivo are demonstrated by significant inhibition of tumor growth. The proposed strategy may provide a new approach to reasonably design and develop safe and efficient photosensitizers for dual phototherapy against cancer.     

Enhanced Antitumor Efficacy by 808 nm Laser‐Induced Synergistic Photothermal and Photodynamic Therapy Based on a Indocyanine‐Green‐Attached W18O49 Nanostructure

A novel nanoplatform based on tungsten oxide (W₁₈O₄₉, WO) and indocyanine green (ICG) for dual‐modal photothermal therapy (PTT) and photodynamic therapy (PDT) has been successfully constructed. In this design, the hierarchical unique nanorod‐bundled W₁₈O₄₉ nanostructures play roles in being not only as an efficient photothermal agent for PTT but also as a potential nanovehicle for ICG molecules via electrostatic adsorption after modified with trimethylammonium groups on their surface. It is found that the ability of ICG to produce cytotoxic reactive oxygen species for PDT is well maintained after being attached on the WO, thus the as‐obtained WO@ICG can achieve a synergistic effect of combined PTT and PDT under single 808 nm near‐infrared (NIR) laser excitation. Notably, compared with PTT or PDT alone, the enhanced HeLa cells lethality of the 808 nm laser triggered dual‐modal therapy is observed. The in vivo animal experiments have shown that WO@ICG has effective solid tumor ablation effect with 808 nm NIR light irradiation, revealing the potential of these nanocomposites as a NIR‐mediated dual‐modal therapeutic platform for cancer treatment.     

Effective Eradication of Tumors by Enhancing Photoacoustic-Imaging-Guided Combined Photothermal Therapy and Ultrasonic Therapy

Exploiting a comprehensive strategy that processes diagnosis and therapeutic functions is desired for eradicating tumors. In this study, two versatile nanoparticles are introduced: one is polyethylene glycol- and polyethyleneimine-modified gold nanorods (mPEG–PEI–AuNRs), and the other is formed by electrostatic interactions between mPEG–PEI and calcium carbonate nanoparticles (mPEG–PEI/CaNPs). These two nanoparticles possess following favorable properties: 1) mPEG–PEI–AuNRs and mPEG–PEI/CaNPs show not only high cell uptake in acidic tumoral pH, but also efficient accumulation in tumors with prolonged circulation. 2) mPEG–PEI/CaNPs can generate carbon dioxide (CO₂) bubbles in acidic tumoral environment and the photoacoustic (PA) signals from mPEG–PEI–AuNRs can be enhanced with the generation of CO₂ bubbles. 3) The tumors can be eradicated by combining photothermal therapy (PTT) with ultrasonic therapy (UST) under the near-infrared (NIR) laser and ultrasonic irradiation with the presence of mPEG–PEI–AuNRs and CO₂ bubbles from mPEG–PEI/CaNPs. The detailed evaluation of cellular uptake, photothermal property of mPEG–PEI–AuNRs, CO₂ bubbles’ generation from mPEG–PEI/CaNPs, imaging, and combined PTT and UST are carried out in vitro or in vivo. This work has great potential usage for diagnosis and treatment in the future.     

Phase‐Change Materials Based Nanoparticles for Controlled Hypoxia Modulation and Enhanced Phototherapy

Tumor hypoxia strengthens tumor resistance to different therapies especially oxygen involved strategies, such as photodynamic therapy (PDT). Herein, the thermal responsive phase change materials (PCM) are utilized to coencapsulate ultrasmall manganese dioxide (sMnO₂) and organic photosensitizer IR780 to obtain IR780‐sMnO₂‐PCM nanoparticles for controlled tumor hypoxia modulation and enhanced phototherapy. The thermal responsive protective PCM layer can not only prevent IR780 from photodegradation, but also immediately release sMnO₂ to decompose endogenous H₂O₂ and generate enough oxygen for PDT under laser irradiation. Owing to the efficient accumulation of IR780‐sMnO₂‐PCM nanoparticles in tumor under intravenous injection as revealed by both florescence imaging and photoacoustic imaging, the tumor hypoxia is greatly relieved. Furthermore, in vivo combined photothermal therapy (PTT) and PDT, IR780‐sMnO₂‐PCM nanoparticles, compared to IR780‐PCM nanoparticles, exhibit better performance in inhibiting tumor growth. The results highlight the promise of IR780‐sMnO₂‐PCM in controlled modulation of tumor hypoxia to overcome current limitations of cancer therapies.     

Gold Nanoshell Nanomicelles for Potential Magnetic Resonance Imaging,Light‐Triggered Drug Release,and Photothermal Therapy

A novel multifunctional drug‐delivery platform is developed based on cholesteryl succinyl silane (CSS) nanomicelles loaded with doxorubicin, Fe₃O₄ magnetic nanoparticles, and gold nanoshells (CDF‐Au‐shell nanomicelles) to combine magnetic resonance (MR) imaging, magnetic‐targeted drug delivery, light‐triggered drug release, and photothermal therapy. The nanomicelles show improved drug‐encapsulation efficiency and loading level, and a good response to magnetic fields, even after the formation of the gold nanoshell. An enhancement for T₂‐weighted MR imaging is observed for the CDF‐Au‐shell nanomicelles. These nanomicelles display surface plasmon absorbance in the near‐infrared (NIR) region, thus exhibiting an NIR (808 nm)‐induced temperature elevation and an NIR light‐triggered and stepwise release behavior of doxorubicin due to the unique characteristics of the CSS nanomicelles. Photothermal cytotoxicity in vitro confirms that the CDF‐Au‐shell nanomicelles cause cell death through photothermal effects only under NIR laser irradiation. Cancer cells incubated with CDF‐Au‐shell nanomicelles show a significant decrease in cell viability only in the presence of both NIR irradiation and a magnetic field, which is attributed to the synergetic effects of the magnetic‐field‐guided drug delivery and the photothermal therapy. Therefore, such multicomponent nanomicelles can be developed as a smart and promising nanosystem that integrates multiple capabilities for effective cancer diagnosis and therapy.     

Photostable Iodinated Silica/Porphyrin Hybrid Nanoparticles with Heavy‐Atom Effect for Wide‐Field Photodynamic/Photothermal Therapy Using Single Light Source

Physical therapies including photodynamic therapy (PDT) and photothermal therapy (PTT) can be effective against diseases that are resistant to chemotherapy and remain as incurable malignancies (for example, multiple myeloma). In this study, to enhance the treatment efficacy for multiple myeloma using the synergetic effect brought about by combining PDT and PTT, iodinated silica/porphyrin hybrid nanoparticles (ISP HNPs) with high photostability are developed. They can generate both ¹O₂ and heat with irradiation from a light‐emitting diode (LED), acting as photosensitizers for PDT/PTT combination treatment. ISP HNPs exhibit the external heavy atom effect, which significantly improves both the quantum yield for ¹O₂ generation and the light‐to‐heat conversion efficiency. The in vivo fluorescence imaging demonstrates that ISP HNPs, modified with folic acid and polyethylene glycol (FA‐PEG‐ISP HNPs), locally accumulate in the tumor after 18 h of their intravenous injection into tumor‐bearing mice. The LED irradiation on the tumor area of the mice injected with FA‐PEG‐ISP HNPs causes necrosis of the tumor tissues, resulting in the inhibition of tumor growth and an improvement in the survival rate.     

Mixed-Metal MOF-Derived Hollow Porous Nanocomposite for Trimodality Imaging Guided Reactive Oxygen Species-Augmented Synergistic Therapy

Here an excellent trimodality imaging-guided synergistic photothermal therapy (PTT)/photodynamic therapy (PDT)/chemodynamic therapy (CDT) is proposed. To this end, a mixed-metal Cu/Zn-metal-organic framework (MOF) is first assembled at room temperature on a nano-scale. Interestingly, heating the MOF results in a Cu^+/2+-coexisting hollow porous structure. Subsequent heating treatment is used to integrate Mn²⁺ and MnO₂ in the presence of manganese(II) acetylacetonate. The hollow composite achieves efficient loading of a photosensitizer, indocyanine green (ICG). Under laser irradiation, the aggregated ICG achieves photothermal imaging and PTT. Once released in the tumor site, ICG exhibits fluorescence imaging and PDT capacity. Cu⁺/Mn²⁺ ions perform Fenton-like reaction with H₂O₂ to produce cytotoxic •OH for the enhanced CDT. Cu²⁺/MnO₂ scavenge glutathione to improve the reactive oxygen species-based therapy, while the formed Mn²⁺ ions enable “turn on” magnetic resonance imaging. Significantly, O₂ is produced from the catalytic decomposition of endogenous H₂O₂ to improve ICG-mediated PDT. Moreover, photothermal-induced local hyperthermia accelerates •OH generation to enhance CDT. This synergistic drug-free antitumor strategy realizes high treatment efficacy and low side effects on normal tissues. Thus, this mixed-metal MOF is an efficient strategy to realize hollow structures for multi-function integration to improve therapeutic capacity.     

Antitumor Platelet‐Mimicking Magnetic Nanoparticles

Nanoparticles possess the potential to revolutionize cancer diagnosis and therapy. The ideal theranostic nanoplatform should own long system circulation and active cancer targeting. Additionally, it should be nontoxic and invisible to the immune system. Here, the authors fabricate an all‐in‐one nanoplatform possessed with these properties for personalized cancer theranostics. Platelet‐derived vesicles (PLT‐vesicles) along with their membrane proteins are collected from mice blood and then coated onto Fe₃O₄ magnetic nanoparticles (MNs). The resulting core–shell PLT‐MNs, which inherit the long circulation and cancer targeting capabilities from the PLT membrane shell and the magnetic and optical absorption properties from the MN core, are finally injected back into the donor mice for enhanced tumor magnetic resonance imaging (MRI) and photothermal therapy (PTT). Meanwhile, it is found that the PTT treatment impels PLT‐MNs targeting to the PTT sites (i.e., tumor sites), and exactly, in turn, the enhanced targeting of PLT‐MNs to tumor sites can improve the PTT effects. In addition, since the PLT membrane coating is obtained from the mice and finally injected into the same mice, PLT‐MNs exhibit stellar immune compatibility. The work presented here provides a new angle on the design of biomimetic nanoparticles for personalized diagnosis and therapy of various diseases.     

Designing Bioinspired 2D MoSe2 Nanosheet for Efficient Photothermal‐Triggered Cancer Immunotherapy with Reprogramming Tumor‐Associated Macrophages

Nonspecific absorption and clearance of nanomaterials during circulation is the major cause for treatment failure in nanomedicine‐based cancer therapy. Therefore, herein bioinspired red blood cell (RBC) membrane is employed to camouflage 2D MoSe₂ nanosheets with high photothermal conversion efficiency to achieve enhanced hemocompatibility and circulation time by preventing macrophage phagocytosis. RBC–MoSe₂‐potentiated photothermal therapy (PTT) demonstrates potent in vivo antitumor efficacy, which triggers the release of tumor‐associated antigens to activate cytotoxic T lymphocytes and inactivate the PD‐1/PD‐L1 pathway to avoid immunologic escape. Furthermore, in the ablated tumor microenvironment, the tumor‐associated macrophages are effectively reprogrammed to tumoricidal M1 phenotype to potentiate the antitumor action. Taken together, this biomimetic functionalization thus provides a substantial advance in personalized PTT‐triggered immunotherapy for clinical translation.     

不同尺寸、形状和组成的金纳米颗粒的光热特性:在癌症治疗中的应用

光热疗法由于其安全和高效的优点,作为一种非破坏性方法在癌症治疗中有广泛的应用前景。光热疗法中,所采用的纳米颗粒在近红外波段的光热转换效率取决于纳米颗粒的光谱吸收特性。采用时域有限差分法对球型、壳型、杆型、片型、笼型、星型和花型等七种不同金纳米颗粒的光谱吸收特性进行了仿真计算,结果表明纳米颗粒的几何参数和结构对其光谱吸收效率和共振波长产生了显著的影响。通过对比七种金纳米颗粒的体积吸收系数,发现金纳米片在近红外波段的光热转换效率优于其他六种金纳米颗粒。从电流密度矢量分布得出,金纳米颗粒内部产生共振电流是导致金纳米颗粒在近红外波段具有明显的单色吸收特性的原因。     

Human HSP70 Promoter‐Based Prussian Blue Nanotheranostics for Thermo‐Controlled Gene Therapy and Synergistic Photothermal Ablation

Realizing precise control of the therapeutic process is crucial for maximizing efficacy and minimizing side effects, especially for strategies involving gene therapy (GT). Herein, a multifunctional Prussian blue (PB) nanotheranostic platform is first designed and then loaded with therapeutic plasmid DNA (HSP70‐p53‐GFP) for near‐infrared (NIR) light‐triggered thermo‐controlled synergistic GT/photothermal therapy (PTT). Due to the unique structure of the PB nanocubes, the resulting PB@PEI/HSP70‐p53‐GFP nanoparticles (NPs) exhibit excellent photothermal properties and pronounced tumor‐contrast performance in T₁/T₂‐weighted magnetic resonance imaging. Both in vitro and in vivo studies demonstrate that mild NIR‐laser irradiation (≈41 °C) activates the HSP70 promoter for tumor suppressor p53‐dependent apoptosis, while strong NIR‐laser irradiation (≈50 °C) induces photothermal ablation for cellular dysregulation and necrosis. Significant synergistic efficacy can be achieved by adjusting the NIR‐laser irradiation (from ≈41 to ≈50 °C), compared to using GT or PTT alone. In addition, in vitro and in vivo toxicity studies demonstrate that PB@PEI/HSP70‐p53‐GFP NPs have good biocompatibility. Therefore, this work provides a promising theranostic approach for controlling combined GT and PTT via the heat‐shock response.     

Intracellular Bottom-up Synthesis of Ultrasmall CuS Nanodots in Cancer Cells for Simultaneous Photothermal Therapy and COX-2 Inactivation

The clinical application of photothermal therapy (PTT) is limited by the accuracy of thermal damage and the risk of tumor metastasis and relapse induced by hyperthermia-related inflammation. Intracellular bottom-up synthesis (iBuS) of CuS nanoparticles from small-molecule precursors inside tumor cells triggered by tumor specific stimuli is a promising strategy to enhance the precision of PTT treatment and reduce the risk of nondegradable metal nanoparticles. Herein, monolocking nanoparticles (MLNPs) with Cu-meloxicam complexes encapsulated by human serum albumin (HSA) are reported, which efficiently form CuS nanodots via the elevated concentration of endogenous H₂S inside tumor cells and meanwhile release meloxicam for anti-inflammatory effects. The intracellular bottom-up fabrication of CuS nanodots is directly visualized by TEM. An enhanced PTT effect is observed with 4T1 cells caused by additional meloxicam-induced inactivation of the COX-2 enzyme. After systemic administration, MLNPs completely ablate tumors under laser exposure, simultaneously inhibiting the inflammation induced by photothermal damage, and can be cleared via the kidney into urine. This strategy provides a new route for activated multimodal therapy, which could be applicable to precisely combat cancer.