A local water molecular-heating strategy for near-infrared long-lifetime imaging-guided photothermal therapy of glioblastoma.

Owing to the strong absorption of water in the near-infrared (NIR) region near 1.0 µm, this wavelength is considered unsuitable as an imaging and analytical signal in biological environments. However, 1.0 µm NIR can be converted into heat and used as a local water-molecular heating strategy for the photothermal therapy of biological tissues. Herein, we describe a Nd-Yb co-doped nanomaterial (water-heating nanoparticles (NPs)) as strong 1.0 µm emissive NPs to target the absorption band of water. Furthermore, introducing Tm ions into the water-heating NPs improve the NIR lifetime, enabling the development of a NIR imaging-guided water-heating probe (water-heating NIR NPs). In the glioblastoma multiforme male mouse model, tumor-targeted water-heating NIR NPs reduce the tumor volume by 78.9% in the presence of high-resolution intracranial NIR long-lifetime imaging. Hence, water-heating NIR NPs can be used as a promising nanomaterial for imaging and photothermal ablation in deep-tissue-bearing tumor therapy.

Recent Advances in Photothermal Therapies Against Cancer and the Role of Membrane Transporter Modulators on the Efficacy of This Approach.

Recently, much research is focused on the use of photothermal therapy (PTT) as an advanced method to treat various types of cancer. The PTT approach primarily utilizes nanoparticles (NPs) made from metals, carbon, or semiconductors that can convert near-infrared laser irradiation, which penetrates tissues, into local heat that induces cancer cell death. An alternative approach is to utilize NPs (such as liposomes) to carry suitable dye molecules to the same end. Numerous studies concerning PTT have shown that local heat released in cancer cells may suppress the expression of membrane transporter proteins such as P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1), thus enhancing cytotoxicity and reverse multidrug resistance. In addition, because NPs may be loaded with different substances, researchers have designed multifunctional NPs for PTT by including several agents such as membrane transporter modulators, anticancer drugs, and photothermal agents. This review will focus on the recent advances in PTT utilizing various types of NPs, and their components and characteristics. In addition, the role of membrane transporters in PTT will be highlighted and different methods of transporter modulation will be summarized from several PTT studies in which multifunctional NPs were used to treat cancers in vitro and in vivo.

Activatable Immunoprotease Nanorestimulator for Second Near-Infrared Photothermal Immunotherapy of Cancer.

Photothermal immunotherapy is a combinational cancer therapy modality, wherein the photothermal process can noninvasively ablate cancer and efficiently trigger cancer immunogenic cell death to ignite antitumor immunity. However, cancer cells can resist the cytotoxic lymphocyte-mediated antitumor effect via expressing serine protease inhibitory proteins (serpins) to deactivate proteolytic immunoproteases. Herein, we report a smart polymer nanoagonist (SPND) with second near-infrared (NIR-II) phototherapeutic ablation and tumor-specific immunoprotease granzyme B (GrB) restimulation for cancer photothermal immunotherapy. SPND has a semiconducting polymer backbone grafted with a small-molecule inhibitor of serpinB9 (Sb9i) via a glutathione (GSH)-cleavable linker. Once in the tumor, Sb9i can be specifically liberated from SPND to inhibit serpinB9, restimulating the activity of GrB to enhance cancer immunotherapy. Moreover, SPND induces photothermal therapy for direct tumor ablation and immunogenic cancer cell death (ICD) under NIR-II photoirradiation. Therefore, such a smart nanoagonist represents a way toward combination photothermal immunotherapy (PTI).

Photodynamic and Photothermal Therapies: Synergy Opportunities for Nanomedicine.

Tumoricidal photodynamic (PDT) and photothermal (PTT) therapies harness light to eliminate cancer cells with spatiotemporal precision by either generating reactive oxygen species or increasing temperature. Great strides have been made in understanding biological effects of PDT and PTT at the cellular, vascular and tumor microenvironmental levels, as well as translating both modalities in the clinic. Emerging evidence suggests that PDT and PTT may synergize due to their different mechanisms of action, and their nonoverlapping toxicity profiles make such combination potentially efficacious. Moreover, PDT/PTT combinations have gained momentum in recent years due to the development of multimodal nanoplatforms that simultaneously incorporate photodynamically- and photothermally active agents. In this review, we discuss how combining PDT and PTT can address the limitations of each modality alone and enhance treatment safety and efficacy. We provide an overview of recent literature featuring dual PDT/PTT nanoparticles and analyze the strengths and limitations of various nanoparticle design strategies. We also detail how treatment sequence and dose may affect cellular states, tumor pathophysiology and drug delivery, ultimately shaping the treatment response. Lastly, we analyze common experimental design pitfalls that complicate preclinical assessment of PDT/PTT combinations and propose rational guidelines to elucidate the mechanisms underlying PDT/PTT interactions.

Analgesic and potentiated photothermal therapy with ropivacaine-loaded hydrogels.

Rationale: Tumor ablation can cause severe pain to patients, but there is no satisfactory means of analgesia available. In addition, recurrence of residual tumors due to incomplete ablation threatens patient safety. Photothermal therapy (PTT), a promising approach for tumor ablation, also faces the aforementioned problems. Therefore, developing novel photothermal agents that can efficiently relieve PTT-associated pain and potentiate the PTT efficacy are urgently needed. Methods: The Pluronic F127 hydrogel doped with indocyanine green (ICG) was served as photothermal agent for PTT. Mouse model that inoculation of tumor near the sciatic nerve was constructed to assess the PTT-evoked pain. Subcutaneous and sciatic nerve vicinal tumor-bearing mice were used to test the efficacy of PTT. Results: PTT-evoked pain depends on an increase in tumor temperature and is accompanied by the activation of TRPV1. A simple introduction of local anesthetic (LA) ropivacaine into ICG-loaded hydrogels relieves PTT-induced pain and exerts long-lasting analgesia compared with opioid analgesia. More interestingly, ropivacaine upregulates major histocompatibility complex class I (MHC-I) in tumor cells by impairing autophagy. Therefore, a hydrogel co-doped with ropivacaine, TLR7 agonist imiquimod and ICG was rationally designed. In the hydrogel system, imiquimod primes tumor-specific CD8+ T cells through promoting DCs maturation, and ropivacaine facilitates tumor cells recognition by primed CD8+ T cells through upregulating MHC-I. Consequently, the hydrogel maximumly increases CD8+ T cells infiltration into tumor and potentiates PTT efficacy. Conclusion: This study for the first time provides an LA-dopped photothermal agents for painless PTT and innovatively proposes that a LA can be used as an immunomodulator to potentiate the PTT efficacy.

Mild photothermal/radiation therapy potentiates ferroptosis effect for ablation of breast cancer via MRI/PA imaging guided all-in-one strategy.

BACKGROUND: Nanotheranostics advances anticancer management by providing therapeutic and diagnostic functions, that combine programmed cell death (PCD) initiation and imaging-guided treatment, thus increasing the efficacy of tumor ablation and efficiently fighting against cancer. However, mild photothermal/radiation therapy with imaging-guided precise mediating PCD in solid tumors, involving processes related to apoptosis and ferroptosis, enhanced the effect of breast cancer inhibition is not fully understood. RESULTS: Herein, targeted peptide conjugated gold nano cages, iRGD-PEG/AuNCs@FePt NPs ternary metallic nanoparticles (Au@FePt NPs) were designed to achieve photoacoustic imaging (PAI)/Magnetic resonance imaging (MRI) guided synergistic therapy. Tumor-targeting Au@FePt forms reactive oxygen species (ROS), initiated by X-ray-induced dynamic therapy (XDT) in collaboration with photothermal therapy (PTT), inducing ferroptosis-augmented apoptosis to realize effective antitumor therapeutics. The relatively high photothermal conversion ability of Au@FePt increases the temperature in the tumor region and hastens Fenton-like processes to achieve enhanced synergistic therapy. Especially, RNA sequencing found Au@FePt inducting the apoptosis pathway in the transcriptome profile. CONCLUSION: Au@FePt combined XDT/PTT therapy activate apoptosis and ferroptosis related proteins in tumors to achieve breast cancer ablation in vitro and in vivo. PAI/MRI images demonstrated Au@FePt has real-time guidance for monitoring synergistic anti-cancer therapy effect. Therefore, we have provided a multifunctional nanotheranostics modality for tumor inhibition and cancer management with high efficacy and limited side effects.

A gold nanoparticle engineered metal-organic framework nanoreactor for combined ferroptosis and mild photothermal therapy.

We demonstrate a gold nanoparticle engineered metal-organic framework nanoreactor with photothermal, glucose oxidase-like and GSH-consuming performance to achieve the accumulation of hydroxyl radicals and the enhancement of the thermal sensitivity for combined ferroptosis and mild photothermal therapy.

Plasmonic nanoparticle-based surface-enhanced Raman spectroscopy-guided photothermal therapy: emerging cancer theranostics.

Optical imaging modalities have emerged as a keystone in oncological research, capable of providing molecular and cellular information on cancer with the advantage of being minimally invasive toward healthy tissues. Photothermal therapy (PTT) has shown great potential, with the exceptional advantages of high specificity and noninvasiveness. Combining surface-enhanced Raman spectroscopy (SERS)-based optical imaging with PTT has shown tremendous potential in cancer theranostics (therapeutics + diagnosis). This comprehensive review article provides up-to-date information by exploring recent works focused mainly on the development of plasmonic nanoparticles for medical applications using SERS-guided PTT, including the fundamental principles behind SERS and the plasmon heating effect for PTT.

A photothermal therapy enhanced mechano-bactericidal hybrid nanostructured surface.

Polymeric materials that have been extensively applied in medical devices, wearable electronics, and food packaging are readily contaminated by bothersome pathogenic bacteria. Bioinspired mechano-bactericidal surfaces can deliver lethal rupture for contacted bacterial cells through mechanical stress. However, the mechano-bactericidal activity based only on polymeric nanostructures is not satisfactory, especially for the Gram-positive strain which is generally more resistant to mechanical lysis. Here, we show that the mechanical bactericidal performance of polymeric nanopillars can be significantly enhanced by the combination of photothermal therapy. We fabricated the nanopillars through the combination of low-cost anodized aluminum oxide (AAO) template-assisted method with an environment-friendly Layer-by-Layer (LbL) assembly technique of tannic acid (TA) and iron ion (Fe3+). The fabricated hybrid nanopillar exhibited remarkable bactericidal performances (more than 99%) toward both Gram-negative Pseudomonas aeruginosa (P. aeruginosa) and stubborn Gram-positive Staphylococcus aureus (S. aureus) bacteria. Notably, this hybrid nanostructured surface displayed excellent biocompatibility for murine L929 fibroblast cells, indicating a selective biocidal activity between bacterial cells and mammalian cells. Thus, the concept and antibacterial system described here present a low-cost, scalable, and highly repeatable strategy for the construction of physical bactericidal nanopillars on polymeric films with high performance and biosafety, but without any risks of causing antibacterial resistance.

Water-soluble polymer brush-substituted squaraine NIR-II dye for efficient photothermal therapy.

Near-infrared II (NIR-II, 1000-1700 nm) fluorescence imaging has the advantages of low light scattering and weak biological autofluorescence compared with conventional NIR (600-900 nm) fluorescence imaging and can obtain a high signal-to-noise ratio in deeper biological tissues, as well as micron-level high resolution. A great deal of effort has been directed toward the construction of conjugated polymers for effective NIR-triggered fluorescence imaging (FI) and photothermal therapy (PTT) combined therapy. However, NIR-II fluorescent materials are mainly nanoparticles prepared by coprecipitation methods, and water-soluble NIR-II materials need to be further developed. In this paper, we synthesized novel water-soluble squaric acid nanoparticles (SQ-POEGMA) with low toxicity and excellent photostability by attaching a water-soluble oligomer (POEGMA) to the small molecule squaric acid through a click chemistry reaction. The photothermal conversion efficiency of SQ-POEGMA is 33% in vitro, which can effectively inhibit the growth of cancer cells with 94% tumor inhibition rate in vivo under 808 nm laser irradiation, while no appreciable side effects were observed.

Temperature-Responsive Nanoassemblies for Self-Regulated Photothermal Therapy and Controlled Copper Release to Accelerate Chronic Wound Healing.

Photothermal therapy (PTT) is an effective therapeutic method against multidrug-resistant bacteria. The heating temperature is of great significance to completely eliminate bacteria but not damage surrounding healthy tissue. To meet the need for chronic wound management, a pH and temperature dual-responsive copper-gold nanoassembly (sCuAu NAs) was constructed by cross-linking the CuAu nanoparticles (CuAu NPs) with small molecules involved in the Edman degradation reaction. At room temperature, the sCuAu NAs could quickly heat up to eliminate the biofilm upon laser irradiation due to the surface plasmon resonance coupling effect. On arriving at the degradation temperature of around 50 °C, the sCuAu NAs are disassembled into CuAu NPs in the wound infection site, which not only prevents overheating but also promotes deep penetration and accelerates copper-ion release to remove residual bacteria and promote wound healing. This study not only provides an effective treatment that can simultaneously alleviate wound infection and accelerate wound healing but also brings up an idea on the development and application of temperature self-regulated photothermal agents in various diseases.

Construction of PEGylated chlorin e6@CuS-Pt theranostic nanoplatforms for nanozymes-enhanced photodynamic-photothermal therapy.

Multifunctional nanoagents with photodynamic therapy (PDT) and photothermal therapy (PTT) functions have shown great promise for cancer treatment, while the design and synthesis of efficient nanoagents remain a challenge. To realize nanozyme-enhanced PDT-PTT combined therapy, herein we have synthesized the Ce6@CuS-Pt/PEG nanoplatforms as a model of efficient nanoagents. Hollow CuS nanospheres with an average diameter of âˆ¼ 200 nm are first synthesized through vulcanization using Cu2O as the precursor. Subsequently, CuS nanospheres are surface-decorated with Pt nanoparticles (NPs) as nanozyme via an in-situ reduction route, followed by modifying the DSPE-PEG5000 and loading the photosensitizer Chlorin e6 (Ce6). The obtained Ce6@CuS-Pt/PEG NPs exhibit high photothermal conversion efficiency (43.08%), good singlet oxygen (1O2) generation ability, and good physiological stability. In addition, Ce6@CuS-Pt/PEG NPs show good catalytic performance due to the presence of Pt nanozyme, which can effectively convert H2O2 to O2 and significantly enhance the production of cytotoxic 1O2. When Ce6@CuS-Pt/PEG NPs dispersion is injected into mice, the tumors can be wholly suppressed owing to nanozyme-enhanced PDT-PTT combined therapy, providing better therapeutic effects compared to single-mode phototherapy. Thus, the present Ce6@CuS-Pt/PEG NPs can act as an efficient multifunctional nanoplatform for tumor therapy.

Visualization of Phototherapy Evolution by Optical Imaging.

Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is a non-invasive and effective approach used for cancer treatment, in which phototherapeutic agents are irradiated with an appropriate light source to produce cytotoxic reactive oxygen species (ROS) or heat to ablate cancer cells. Unfortunately, traditional phototherapy lacks a facile imaging method to monitor the therapeutic process and efficiency in real time, usually leading to severe side effects due to high levels of ROS and hyperthermia. To realize precise cancer treatment methods, it is highly desired to develop phototherapeutic agents possessing an imaging ability to evaluate the therapeutic process and efficacy in real time during cancer phototherapy. Recently, a series of self-reporting phototherapeutic agents were reported to monitor PDT and PTT processes by combining optical imaging technologies with phototherapy. Due to the real-time feedback provided by optical imaging technology, therapeutic responses or dynamic changes in the tumor microenvironment could be evaluated in a timely manner, thereby achieving personalized precision treatment and minimizing toxic side effects. In this review, we focus on the advances in the development of self-reporting phototherapeutic agents for a cancer phototherapy evaluation based on optical imaging technology to realize precision cancer treatments. Additionally, we propose the current challenges and future directions of self-reporting agents for precision medicine.

Carbon dots-mediated synthesis of gold nanodendrites with extended absorption into NIR-II window for in vivo photothermal therapy.

BACKGROUND: Photothermal therapy (PTT) in the second near-infrared (NIR-II) window has attracted extensive attention due to the benefits in high maximum permissible exposure and penetration depth. Current photothermal agents generally show a broadband absorption accompanied by a gradual attenuation of absorption in the NIR-II window, leading to poor effect of PTT. It remains a great challenge to gain photothermal agents with strong and characteristic absorption in NIR-II regions. To overcome this problem, based on carbon dots (CDs)-mediated growth strategy, we proposed a simple and feasible approach to prepare plasmonic gold nanodendrites (AuNDs) with NIR-II absorption to enhance the therapeutic effect of PTT. RESULTS: By rationally regulating the size and branch length of AuNDs, the AuNDs exhibited a broadband absorption from 300 to 1350 nm, with two characteristic absorption peaks located at 1077 and 1265 nm. The AuNDs demonstrated desired optical photothermal conversion efficiency (38.0%), which was further applied in NIR-II photoacoustic imaging (PAI) and PTT in human colon cancer cells (HCT 116)-tumor-bearing mice model. The tumor cells could be effectively eliminated in vivo under 1064 nm laser irradiation by the guidance of PAI. CONCLUSIONS: We reported a simple but powerful synthetic method to obtain the unique AuNDs with strong and characteristic absorption peaks in the NIR-II window. This study provides a promising solution to tuning the growth of nanoparticles for bioimaging and phototherapy in the NIR-II window.

Revealing the Effect of Photothermal Therapy on Human Breast Cancer Cells: A Combined Study from Mechanical Properties to Membrane HSP70.

Hyperthermia-induced overexpression of heat shock protein 70 (HSP70) leads to the thermoresistance of cancer cells and reduces the efficiency of photothermal therapy (PTT). In contrast, cancer cell-specific membrane-associated HSP70 has been proven to activate antitumor immune responses. The dual effect of HSP70 on cancer cells inspires us that in-depth research of membrane HSP70 (mHSP70) during PTT treatment is essential. In this work, a PTT treatment platform for human breast cancer cells (MCF-7 cells) based on a mPEG-NH2-modified polydopamine (PDA)-coated gold nanorod core-shell structure (GNR@PDA-PEG) is developed. Using the force-distance curve-based atomic force microscopy (FD-based AFM), we gain insight into the PTT-induced changes in the morphology, mechanical properties, and mHSP70 expression and distribution of individual MCF-7 cells with high-resolution at the single-cell level. PTT treatment causes pseudopod contraction of MCF-7 cells and generates a high level of intracellular reactive oxygen species, which severely disrupt the cytoskeleton, leading to a decrease in cellular mechanical properties. The adhesion maps, which are recorded by aptamer A8 functional probes using FD-based AFM, reveal that PTT treatment causes a significant upregulation of mHSP70 expression and it starts to exhibit a partial aggregation distribution on the MCF-7 cell surface. This work not only exemplifies that AFM can be a powerful tool for detecting changes in cancer cells during PTT treatment but also provides a better view for targeting mHSP70 for cancer therapy.

Intelligent Pd1.7Bi@CeO2 Nanosystem with Dual-Enzyme-Mimetic Activities for Cancer Hypoxia Relief and Synergistic Photothermal/Photodynamic/Chemodynamic Therapy.

Reactive oxygen species-mediated therapeutic strategies, including chemodynamic therapy (CDT) and photodynamic therapy (PDT), have exhibited translational promise for effective cancer management. However, monotherapy often ends up with the incomplete elimination of the entire tumor due to inherent limitations. Herein, we report a core-shell-structured Pd1.7Bi@CeO2-ICG (PBCI) nanoplatform constructed by a facile and effective strategy for synergistic CDT, PDT, and photothermal therapy. In the system, both Pd1.7Bi and CeO2 constituents exhibit peroxidase- and catalase-like characteristics, which not only generate cytotoxic hydroxyl radicals (•OH) for CDT but also produce O2 in situ and relieve tumor hypoxia for enhanced PDT. Furthermore, upon 808 nm laser irradiation, Pd1.7Bi@CeO2 and indocyanine green (ICG) coordinately prompt favorable photothermia, resulting in thermodynamically amplified catalytic activities. Meanwhile, PBCI is a contrast agent for near-infrared fluorescence imaging to determine the optimal laser therapeutic window in vivo. Consequently, effective tumor elimination was realized through the above-combined functions. The as-synthesized unitary PBCI theranostic nanoplatform represents a potential one-size-fits-all approach in multimodal synergistic therapy of hypoxic tumors.

A TMVP1-modified near-infrared nanoprobe: molecular imaging for tumor metastasis in sentinel lymph node and targeted enhanced photothermal therapy.

BACKGROUND: TMVP1 is a novel tumor targeting polypeptide screened by our laboratory with a core sequence of five amino acids LARGR. It specially binds to vascular endothelial growth factor receptor-3 (VEGFR-3), which is mainly expressed on neo-lymphatic vessels in sentinel lymph node (SLN) with tumor metastasis in adults. Here, we prepared a targeted nanoprobe using TMVP1-modified nanomaterials for tumor metastasis SLN imaging. RESULTS: In this study, TMVP1-modified polymer nanomaterials were loaded with the near-infrared (NIR) fluorescent dye, indocyanine green (ICG), to prepare a molecular imaging TMVP1-ICG nanoparticles (NPs) to identify tumor metastasis in SLN at molecular level. TMVP1-ICG-NPs were successfully prepared using the nano-precipitation method. The particle diameter, morphology, drug encapsulation efficiency, UV absorption spectrum, cytotoxicity, safety, and pharmacokinetic properties were determined. The TMVP1-ICG-NPs had a diameter of approximately 130 nm and an ICG loading rate of 70%. In vitro cell experiments and in vivo mouse experiments confirmed that TMVP1-ICG-NPs have good targeting ability to tumors in situ and to SLN with tumor metastasis by binding to VEGFR-3. Effective photothermal therapy (PTT) with TMVP1-ICG-NPs was confirmed in vitro and in vivo. As expected, TMVP1-ICG-NPs improved ICG blood stability, targeted tumor metastasis to SLN, and enhanced PTT/photodynamic (PDT) therapy, without obvious cytotoxicity, making it a promising theranostic nanomedicine. CONCLUSION: TMVP1-ICG-NPs identified SLN with tumor metastasis and were used to perform imaging-guided PTT, which makes it a promising strategy for providing real-time NIR fluorescence imaging and intraoperative PTT for patients with SLN metastasis.

Multifunctional fluorescent mesoporous carbon nanoprobe for MMP-2-activated cancer cell imaging and targeted photothermal therapy.

The integration of cancer imaging with therapy in a simple system is warranted for precise cancer therapy. In this study, carboxyl-functionalized mesoporous carbon nanospheres (MCN) which are efficient photothermal agents and excellent fluorescence quenchers, were used for cancer cell imaging and selective photothermal therapy (PTT) applications. Using MCN, a matrix metalloproteinase-2 (MMP-2)- responsive theranostic nanoprobe was generated by functionalizing an MMP-2-specific fluorescent-labeled PLGVR sequence on the surface of MCN. The nanoprobe not only can be used to detect MMP-2 with a low detection limit of 0.3 pg mL-1, but also can achieve the sensitive intracellular MMP-2 imaging in living cells, validating the differentiation of cancer cells from healthy cells based on the recovered fluorescence intensity. More importantly, selective cancer PTT was achieved using MMP-2-triggered cancer cell imaging. Our in vitro studies showed that by regulating the power density and irradiation time, the nanoprobe can effectively kill cancer cells via PTT. Our strategy opens new avenues for precision medicine, especially phototherapy.

Fullerene Covalent Passivation of Black Phosphorus Nanosheets toward Enhanced Near-Infrared-II Photothermal Therapy.

Photothermal therapy (PTT) triggered by near-infrared-II (NIR-II, 1000-1700 nm) light is developed as a potential tumor therapy technique with deeper tissue penetration capacity and higher allowable laser power density of the skin than NIR-I (750-1000 nm) biowindow. Black phosphorus (BP) with excellent biocompatibility and favorable biodegradability demonstrates promising applications in PTT but suffers from low ambient stability and limited photothermal conversion efficiency (PCE), and utilization of BP in NIR-II PTT is scarcely reported. Herein, we develop novel fullerene covalently modified few-layer BP nanosheets (BPNSs) with ∼9-layer thickness through an easy one-step esterification process (abbreviated BP-ester-C60), bringing about the dramatically enhanced ambient stability of BPNSs due to bonding of the hydrophobic C60 with high stability and the lone electron pair on the phosphorus atom. BP-ester-C60 is then applied as a photosensitizer in NIR-II PTT, delivering a much higher PCE than the pristine BPNSs. Under 1064 nm NIR-II laser irradiation, in vitro and in vivo antitumor studies reveal that BP-ester-C60 exhibits dramatically enhanced PTT efficacy with considerable biosafety relative to the pristine BPNSs. This is interpreted by the boost of NIR light absorption on account of the modulation of the band energy level resulting from intramolecular electron transfer from BPNSs to C60.

NIR absorptive croconic acid/quercetin/CaO2 nanoplatform for tumor calcium overload therapy combined mild photothermal therapy.

With excellent biocompatibility, stable chemical and optical properties, small organic molecules-based agents have always been a research hotspot in cancer photothermal therapy (PTT). In this work, a novel croconic acid-based molecule (CR) was designed and synthesized as an ideal photothermal agent (PTA), which showed abundant near-infrared (NIR) light absorption, high photothermal conversion ability, and excellent photothermal stability. By loading CR and quercetin (Qu) in CaO2, and coated with DSPE-PEG2000, a multifunctional theranostic nanoparticle (CCQ) was successfully prepared for calcium overloading mitochondrial metabolism inhibition synergetic mild PTT. Upon entering tumor microenvironment, CCQ can produce abundant H2O2 and a large amount of calcium ions, which lead to the imbalance of calcium concentration in the internal environment of tumor cells and induced mitochondrial apoptosis. With the existence of Qu, CCQ can effectively inhibit the expression of heat shock proteins (Hsp) during the PTT process, which weaken the heat resistance of tumors, ablate tumors at lower temperature (~45 °C), and reduce the damage to normal tissues. Guided by photoacoustic imaging (PAI), CCQ showed excellent multimodal therapeutic effect of tumors. This study provided a novel CR organic molecule-based theranostic nanoplatform that can be used to treat tumors via calcium overload therapy synergetic PTT at safe temperatures, which has promising potential for the future clinical cancer treatment.