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Phototheranostics, which consists of photothermal therapy (PTT) and photodynamic therapy (PDT), has exhibited huge potential in preventing the development of cancer. Then, phototheranostics utilizing photoacoustic imaging (PAI) in the second near-infrared (NIR-II) region, combined with high photothermal conversion efficiency (PCE) and cytotoxic reactive oxygen species (ROS) generation. In this work, we designed and prepared a fused-ring acceptor–donor–acceptor (A–D–A) molecule structure named INPIC-4F NP, known for its strong NIR light absorption and hydrophobic properties. INPIC-4F NPs in aqueous solution behaved excellently with NIR-II and PAI ability with NIR absorption at 808 nm and its fluorescence peaked at ∼1000 nm. With singlet oxygen in a quantum yield of 11%, INPIC-4F NPs showed potential for PDT ability. Moreover, INPIC-4F showed a PCE value of 83% under laser irradiation, which was obviously higher than that caused by photothermal agents, demonstrating an excellent PTT capacity. Combining previous and present results, INPIC-4F nanoparticles could improve the treatment effect for cancer through fluorescence imaging-guided photothermal and photodynamic synergistic therapy. [ABSTRACT FROM AUTHOR]

As a novel therapeutic approach, photothermal therapy (PTT) combined with chemotherapy can synergistically produce antitumor effects. Herein, dithiodipropionic acid (DTDP) was used as a donor of disulfide bonds sensitive to the tumor microenvironment for establishing chemical bonding between the photosensitizer indocyanine green amino (ICG-NH2) and acidified single-walled carbon nanotubes (CNTs). The CNT surface was then coated with conjugates (HD) formed by the targeted modifier hyaluronic acid (HA) and 1,2-tetragacylphosphatidyl ethanolamine (DMPE). After doxorubicin hydrochloride (DOX), used as the model drug, was loaded by CNT carriers, functional nano-delivery systems (HD/CNTs-SS-ICG@DOX) were developed. Nanosystems can effectively induce tumor cell (MCF-7) death in vitro by accelerating cell apoptosis, affecting cell cycle distribution and reactive oxygen species (ROS) production. The in vivo antitumor activity results in tumor-bearing model mice, further verifying that HD/CNTs-SS-ICG@DOX inhibited tumor growth most significantly by mediating a synergistic effect between chemotherapy and PTT, while various functional nanosystems have shown good biological tissue safety. In conclusion, the composite CNT delivery systems developed in this study possess the features of high biocompatibility, targeted delivery, and responsive drug release, and can achieve the efficient coordination of chemotherapy and PTT, with broad application prospects in cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Diclofenac sodium (DS) and celecoxib (CEL) are primary anti-inflammatory agents used in the treatment of osteoarthritis (OA). Formulating these drugs into extended-release versions can effectively address the issue of multiple daily doses. In this study, we designed and synthesized a novel poly(lactic-co-glycolic acid) (PLGA) nanoliposome as a dual-drug delivery sustained-release formulation (PPLs-DS-CEL) to achieve long-lasting synergistic treatment of OA with both DS and CEL. Methods: PPLs-DS-CEL was synthesized by the reverse evaporation method and evaluated for its physicochemical properties, encapsulation efficiency, drug release kinetics and biological properties. A rat OA model was established to assess the therapeutic efficacy and biosafety of PPLs-DS-CEL. Results: The particle size of PPLs-DS-CEL was 218.36 ± 6.27 nm, with a potential of 32.56 ± 3.28 mv, indicating a homogeneous vesicle size. The encapsulation of DS and CEL by PPLs-DS-CEL was 95.18 ± 4.43% and 93.63 ± 5.11%, with drug loading of 9.56 ± 0.32% and 9.68 ± 0.34%, respectively. PPLs-DS-CEL exhibited low cytotoxicity and hemolysis, and was able to achieve long-lasting synergistic analgesic and anti-inflammatory therapeutic effects in OA through slow release of DS and CEL, demonstrating good biosafety properties. Conclusion: This study developed a novel sustained-release nanoliposomes formulation capable of co-loading two drugs for the long-acting synergistic treatment of OA. It offers a new and effective therapeutic strategy for OA treatment in the clinic settings and presents a promising approach for drug delivery systems. [ABSTRACT FROM AUTHOR]

[Display omitted] • Hydrogel containing viologen-based hyperbranched polyamide amines with dual drug loading capacity. • Wearable Patch (Patch-DT) uses hydrogel as the drug-carrying cathode and magnesium flakes as the anode. • Patch-DT enables release of two drugs simultaneously, overcoming the limitations of monotherapy. • Visible drug monitoring through wearable Patch's electrochromic properties. Wearable drug delivery systems (DDS) have made significant advancements in the field of precision medicine, offering precise regulation of drug dosage, location, and timing. The performance qualities that wearable DDS has always strived for are simplicity, efficiency, and intelligence. This paper proposes a wearable dual-drug synergistic release patch. The patch is powered by a built-in magnesium battery and utilizes a hydrogel containing viologen-based hyperbranched polyamidoamine as both a cathode material and an integrated drug reservoir. This design allows for the simultaneous release of both dexamethasone and tannic acid, overcoming the limitations of monotherapy and ensuring effective synergy for on-demand therapy. In a mouse model with praziquimod-induced psoriasis, the patch demonstrated therapeutic efficacy at a low voltage. The inflammatory skin returned to normal after 5 days with the on-demand release of dual drugs. This work provides a promising treatment option considering its straightforward construction and the therapeutic advantages of dual-drug synergy. [ABSTRACT FROM AUTHOR]

Copper-based nanomaterials demonstrate promising potential in cancer therapy. Cu+ efficiently triggers a Fenton-like reaction and further consumes the high level of glutathione, initiating chemical dynamic therapy (CDT) and ferroptosis. Cuproptosis, a newly identified cell death modality that represents a great prospect in cancer therapy, is activated. However, active homeostatic systems rigorously keep copper levels within cells exceptionally low, which hinders the application of cooper nanomaterials-based therapy. Herein, a novel strategy of CRISPR-Cas9 RNP nanocarrier to deliver cuprous ions and suppress the expression of copper transporter protein ATP7A for maintaining a high level of copper in cytoplasmic fluid is developed. The Cu 2 O and organosilica shell would degrade under the high level of glutathione and weak acidic environment, further releasing RNP and Cu+. The liberated Cu+ triggered a Fenton-like reaction for CDT and partially transformed to Cu2+, consuming intracellular GSH and initiating cuproptosis and ferroptosis efficiently. Meanwhile, the release of RNP effectively reduced the expression of copper transporter ATP7A, subsequently increasing the accumulation of cooper and enhancing the efficacy of CDT, cuproptosis, and ferroptosis. Such tumor microenvironment responsive multimodal nanoplatform opens an ingenious avenue for colorectal cancer therapy based on gene editing enhanced synergistic cuproptosis/CDT/ferroptosis. A Cu 2 O-based, CRISPR-Cas9 RNP-doped, organosilica shell-coated and folic acid modified polymorphous therapeutic nanomedicine (RNP@Cu 2 O@SPF) was prepared to convey RNP and Cu+ into tumor cells for gene editing promoted synergistic cuproptosis/chemodynamic/ferroptosis. [Display omitted] [ABSTRACT FROM AUTHOR]

The reactive oxygen species (ROS) generation from photosensitizer in photodynamic therapy (PDT) is limited by tumor hypoxia. Even type-I photosensitizers, e.g., sulfur-substituted Nile blue, still rely on oxygen as the main center for transferring electrons to generate ROS. Cutting off the pathway of oxygen consumption in tumor can help photosensitizers overcome the limitation of low oxygen, in order to efficiently generate more ROS. It is known that glycolysis inhibitor 3-bromopyruvic acid (3-BP), which could specially target mitochondria, can provide more oxygen by inhibiting oxidative phosphorylation. Herein, we successfully designed and synthesized a new 3-BP-coupled sulfur-substituted Nile blue as prodrug (NBBP) for chemical/photodynamic synergistic therapy. Major results indicated that the protons in tumor catalyzed the hydrolysis of NBBP, inhibited photoinduced electron transfer between 3-BP and the photosensitizer in NBBP and further assisted the photosensitizer to be localized in mitochondria, utilizing local oxygen as much as possible and kill tumor cells more efficiently. Moreover, the glycolysis inhibition-induced autophagy was combined with PDT-induced autophagy, which could promote the deaths of tumor cells. Unlike other remedies exploiting nanomaterials, this construction method of NBBP achieves the efficient synergy of photodynamic therapy and glycolysis inhibition, stronger than their theoretical addition, in spatiotemporal dimensions. Our study provides not only a highly efficient platform for tumor therapy but also a design approach for prodrugs with synergistic effects. [ABSTRACT FROM AUTHOR]

Cuproptosis efficiency is severely limited by insufficient Cu+ contents in tumors due to the easy oxidation of Cu+ into Cu2+ and the copper efflux mechanism. Herein, we develop a copper nanocarrier (MoSe2/CuO2) that can significantly enhance intracellular Cu+ for self-boosting cuproptosis-based synergistic antitumor therapy. Upon endocytosis by cancer cells, the acidic tumor microenvironment (TME) triggers the degradation of MoSe2/CuO2 to release Cu2+. MoSe2 then acts as a cocatalyst that promotes the reduction of released Cu2+ to Cu+, while oxidizing active Mo4+ to Mo6+, thereby triggering cuproptosis. Importantly, the produced Mo6+ is further returned to Mo4+ by endogenous glutathione (GSH) depletion, enhancing the cocatalytic effects of MoSe2 and resulting in a continuous Cu+ generation for self-boosting cuproptosis. Meanwhile, GSH-enhanced cocatalysis and MoSe2-mediated photothermal effect can significantly promote Cu-Fenton reactions, which not only downregulate Cu-ATPase to reduce Cu+ efflux and aggravate cuproptosis with higher efficacy but also activate caspase-3 to promote cell apoptosis. MoSe2/CuO2 exhibits excellent antitumor effects (94.9% tumor growth inhibition) and biosafety effects in vitro and in vivo. This work presents a strategy that enables high levels of Cu+ delivery by enhancing generation and reducing efflux for self-boosting cuproptosis–apoptosis synergistic therapy. [ABSTRACT FROM AUTHOR]

Nanocatalytic therapeutic agents with triple synergistic treatment modes of chemodynamic therapy (CDT), photothermal therapy (PTT) and photodynamic therapy (PDT) are emerging nanomaterials in malignancy treatment. Nevertheless, the passive diffusion and transport of nanomaterials result in poor permeability in tumor lesions, severely affecting the effectiveness of synergistic therapy. Herein, a dual‐source‐driven parachute‐like Au2Pt@PMO@ICG Janus nanomotor (APIJNS) is prepared by an interfacial energy‐mediated anisotropic growth strategy for PTT‐mediated CDT/PDT triple synergistic cancer therapy. Such nanomotor can realize self‐thermophoresis drive under the trigger of near‐infrared light, which can effectively enhance the active permeability and uptake of the APIJNS in the tumor tissue, thus achieving efficient PTT/PDT/CDT synergistic therapeutic effect. In addition, parachute‐like APIJNS exhibits high‐efficiency catalase (CAT)‐like activity and can catalyze the overexpressed H2O2 in the tumor microenvironment (TME) to generate oxygen (O2), not only alleviating the hypoxia in the tumor lesion, but also converting it into singlet oxygen (1O2) to activate the photosensitizer ICG, achieving PDT. This work provides new ideas for enhancing triple synergistic cancer therapy by improving tumor permeability with dual‐drive Janus nanomotors based on dual noble metal nanozymes. [ABSTRACT FROM AUTHOR]

The combination of traditional chemotherapy (CT) with emerging photothermal therapy (PTT) can enhance therapeutic efficiency to tumors with minimimal side effects. Herein, a thermosensitive nanoagent (Au@HGC-DOX-ICG) was successfully fabricated based on the encapsulation of a CT drug (Doxorubicin, DOX) and a photothermal agent (Indocyanine green, ICG) into hexanoyl glycol chitosan (HGC)/gold composite nanoparticles (Au@HGC) for the PTT/CT synergistic therapy of tumors. Under 808 nm laser irradiation, ICG in Au@HGC-DOX-ICG converts light energy into local heat, inducing PTT treatment and the shrinkage of thermosensitive HGC layers coated on gold nanoparticles (AuNPs) to promote the release of loaded DOX, thus achieving excellent cytotoxicity against HeLa and SiHa cell lines, superior to the results of a single PTT or CT modalities. In vivo HeLa tumor-bearing mice models validated the excellent PTT/CT synergistic therapeutic efficiency of the nanoagent. The developed Au@HGC-DOX-ICG nanoagent exhibits promise for applications in PTT/CT synergistic tumor therapy, especially in deep tissue. [ABSTRACT FROM AUTHOR]

Photothermal, photodynamic and sonodynamic cancer therapies offer opportunities for precise tumor ablation and reduce side effects. The cyclic guanylate adenylate synthase-stimulator of interferon genes (cGAS-STING) pathway has been considered a potential target to stimulate the immune system in patients and achieve a sustained immune response. Combining photothermal, photodynamic and sonodynamic therapies with cGAS-STING agonists represents a newly developed cancer treatment demonstrating noticeable innovation in its impact on the immune system. Recent reviews have concentrated on diverse materials and their function in cancer therapy. In this review, we focus on the molecular mechanism of photothermal, photodynamic and sonodynamic cancer therapies and the connected role of cGAS-STING agonists in treating cancer. [ABSTRACT FROM AUTHOR]

Nanomedicine‐induced cancer cell death has become a prominent area of research in the life sciences field in recent years. The concept of cuproptosis was first proposed in 2022. Copper homeostasis in organisms is tightly regulated by protein transporters and molecular chaperones. Disruptions in copper homeostasis can adversely affect mitochondrial respiration and disrupt other physiological processes, leading to cytotoxicity. Therefore, researchers have designed and refined copper‐based nanomaterials to induce cuproptosis and assess their effects on cancer treatment. While several reviews on cuproptosis exist, they primarily delve into its molecular mechanisms. This review begins with elucidating the metabolism and homeostasis of copper in the body. Subsequently, the latest advancements in copper nanomaterial‐induced cuproptosis for cancer treatment and antimicrobial purposes is summarized. Finally, a comprehensive summary and outlook on the subject is provided. The goal with this review is to assist researchers in gaining a deeper understanding of the interaction between nanomaterials and cuproptosis, thereby offering new perspectives for designing novel nanomaterials to induce cuproptosis. [ABSTRACT FROM AUTHOR]

The research trend of cancer treatment has shifted from monotherapy to combination therapy. In this study, mesoporous bioactive glass (MBG) was used as a drug carrier, that combined photothermal therapy (PTT) and photodynamic therapy (PDT). The condition for photothermal therapy to achieve effective treatment is local hyperthermia in a short time, to achieve that, this study chose bismuth nanoparticle, an element that has good biocompatibility and high photothermal conversion efficiency (PCE = ∼40 %) under the irradiation of near-infrared (NIR) laser, as photothermal agent. A photosensitizer-indocyanine green (ICG), which has good biocompatibility and can be triggered with NIR to generate reactive oxygen species (ROS), was also loaded in MBG. The MBG loaded with a photothermal agent and photosensitizer was named MBG@Bi-ICG. MBG@Bi has an excellent PCE = 47.67 %, which helps to reach enough temperature for therapeutic effect. In combination with ICG, MBG@Bi-ICG achieves great cytotoxicity against A549 cancer cells after the irradiation of 808 nm laser source (IC50 = 96.5 μg/mL), due to the synergistic effect of local hyperthermia generated by the photothermal agent-bismuth nanoparticle, and ROS generated by photosensitizer-ICG. [ABSTRACT FROM AUTHOR]

PD‐1/PD‐L1 inhibitors have emerged as standard treatments for advanced solid tumors; however, challenges such as a low overall response rate and systemic side effects impede their implementation. Hypoxia drives the remodeling of the tumor microenvironment, which is a leading reason for the failure of immunotherapies. Despite some reported strategies to alleviate hypoxia, their individual limitations constrain further improvements. Herein, a novel two‐pronged strategy is presented to efficiently address hypoxia by simultaneously adopting atovaquone (ATO, inhibiting oxygen consumption) and oxyhemoglobin (HbO2, directly supplementing oxygen) within a multifunctional aggregate termed NPs‐aPD‐1/HbO2/ATO. In addition to eliminating hypoxia with these two components, this smart aggregate also includes albumin and an ROS‐responsive cross‐linker as a controlled release scaffold, along with PD‐1 antibody (aPD‐1) for immunotherapy. Intriguingly, NPs‐aPD‐1/HbO2/ATO demonstrates exceptional tumor targeting in vivo, exhibiting ≈4.2 fold higher accumulation in tumors than in the liver. Consequently, this aggregate not only effectively mitigates hypoxia and significantly assists aPD‐1 immunotherapy but also simultaneously resolves the targeting and systemic toxicity issues associated with individual administration of each component. This study proposes substantial implications for drug‐targeted delivery, addressing tumor hypoxia and advancing immunotherapy, providing valuable insights for advancing cancer treatment strategies. [ABSTRACT FROM AUTHOR]

Junzi Chen,* Yumin Xiang,* Rong Bao, Yuyi Zheng, Yingxi Fang, Jiajia Feng, Di Wu, Xiaojie Chen Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, 310053, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaojie Chen; Di Wu, Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, People’s Republic of China, Email chenxiaojie0902@163.com; wudichem@zju.edu.cnIntroduction: Breast cancer ranks among the most prevalent cancers in women, characterized by significant morbidity, disability, and mortality. Presently, chemotherapy is the principal clinical approach for treating breast cancer; however, it is constrained by limited targeting capability and an inadequate therapeutic index. Photothermal therapy, as a non-invasive approach, offers the potential to be combined with chemotherapy to improve tumor cellular uptake and tissue penetration. In this research, a mesoporous polydopamine-coated gold nanorod nanoplatform, encapsulating doxorubicin (Au@mPDA@DOX), was developed.Methods: This nanoplatform was constructed by surface coating mesoporous polydopamine (mPDA) onto gold nanorods, and doxorubicin (DOX) was encapsulated in Au@mPDA owing to π-π stacking between mPDA and DOX. The dynamic diameter, zeta potential, absorbance, photothermal conversion ability, and drug release behavior were determined. The cellular uptake, cytotoxicity, deep penetration, and anti-tumor effects were subsequently investigated in 4T1 cells. After that, fluorescence imaging, photothermal imaging and pharmacodynamics studies were utilized to evaluate the anti-tumor effects in tumor-bearing mice model.Results: This nanoplatform exhibited high drug loading capacity, excellent photothermal conversion and, importantly, pH/photothermal dual-responsive drug release behavior. The in vitro results revealed enhanced photothermal-facilitated cellular uptake, drug release and tumor penetration of Au@mPDA@DOX under near-infrared irradiation. In vivo studies confirmed that, compared with monotherapy with either chemotherapy or photothermal therapy, the anti-tumor effects of Au@mPDA@DOX are synergistically improved.Conclusion: Together with good biosafety and biocompatibility, the Au@mPDA@DOX nanoplatform provides an alternative method for safe and synergistic treatment of breast cancer. Keywords: breast cancer, synergistic therapy, polydopamine, gold nanorod, chemotherapy

Yuhang Tian,1 Xiang He,1 Yanchi Yuan,1 Shijie Zhang,2 Chunyue Wang,1 Jialin Dong,1 Zhao Liu,1 Hui Jing1 1Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, 150081, People’s Republic of China; 2Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, People’s Republic of ChinaCorrespondence: Hui Jing, Department of Ultrasound, Harbin Medical University Cancer Hospital, 150 Haping Road, Nangang District, Harbin, 150081, People’s Republic of China, Email jinghuihrb@163.comBackground: Triple negative breast cancer (TNBC) is one of the worst prognosis types of breast cancer that urgently needs effective therapy methods. However, cancer is a complicated disease that usually requires multiple treatment modalities.Methods: A tumor microenvironment (TME)-responsive PFC/TRIM37@Fe-TA@HA (abbreviated as PTFTH) nanoplatform was constructed by coating Fe3+ and tannic acid (TA) on the surface of TRIM37-siRNA loaded phase-transition perfluorocarbon (PFC) nanodroplets and further modifying them with hyaluronic acid (HA) to achieve tumor-specific mild photothermal/gene/ferroptosis synergistic therapy (MPTT/GT/ Ferroptosis) in vitro. Once internalized into tumor cells through CD44 receptor-mediated active targeting, the HA shell of PTFTH would be preliminarily disassembled by hyaluronidase (HAase) to expose the Fe-TA metal-phenolic networks (MPNs), which would further degrade in response to an acidic lysosomal environment, leading to HAase/pH dual-responsive release of Fe3+ and PFC/TRIM37.Results: PTFTH showed good biocompatibility in vitro. On the one hand, the released Fe3+ could deplete the overexpressed glutathione (GSH) through redox reactions and produce Fe2+, which in turn converts endogenous H2O2 into highly cytotoxic hydroxyl radicals (•OH) for chemodynamic therapy (CDT). On the other hand, the local hyperthermia generated by PTFTH under 808 nm laser irradiation could not only improve CDT efficacy through accelerating the Fe2+-mediated Fenton reaction, but also enhance TRIM37-siRNA delivery for gene therapy (GT). The consumption of GSH and accumulation of •OH synergistically augmented intracellular oxidative stress, resulting in substantial tumor cell ferroptosis. Moreover, PTFTH possessed outstanding contrast enhanced ultrasound (CEUS), photoacoustic imaging (PAI) and magnetic resonance imaging (MRI) ability.Conclusion: This PTFTH based multiple-mode therapeutic strategy has successfully achieved a synergistic anticancer effect in vitro and has the potential to be translated into clinical application for tumor therapy in future.Keywords: mild photothermal therapy, gene therapy, ferroptosis, synergistic therapy, multimodal imaging

As a “cold tumor”, triple-negative breast cancer (TNBC) exhibits limited responsiveness to current immunotherapy. How to enhance the immunogenicity and reverse the immunosuppressive microenvironment of TNBC remain a formidable challenge. Herein, an “in situ nanovaccine” Au/CuNDs-R848 was designed for imaging-guided photothermal therapy (PTT)/chemodynamic therapy (CDT) synergistic therapy to trigger dual immunoregulatory effects on TNBC. On the one hand, Au/CuNDs-R848 served as a promising photothermal agent and nanozyme, achieving PTT and photothermal-enhanced CDT against the primary tumor of TNBC. Meanwhile, the released antigens and damage-associated molecular patterns (DAMPs) promoted the maturation of dendritic cells (DCs) and facilitated the infiltration of T lymphocytes. Thus, Au/CuNDs-R848 played a role as an “in situ nanovaccine” to enhance the immunogenicity of TNBC by inducing immunogenic cell death (ICD). On the other hand, the nanovaccine suppressed the myeloid‐derived suppressor cells (MDSCs), thereby reversing the immunosuppressive microenvironment. Through the dual immunoregulation, “cold tumor” was transformed into a “hot tumor”, not only implementing a “turning foes to friends” therapeutic strategy but also enhancing immunotherapy against metastatic TNBC. Furthermore, Au/CuNDs-R848 acted as an excellent nanoprobe, enabling high-resolution near-infrared fluorescence and computed tomography imaging for precise visualization of TNBC. This feature offers potential applications in clinical cancer detection and surgical guidance. Collectively, this work provides an effective strategy for enhancing immune response and offers novel insights into the potential clinical applications for tumor immunotherapy.

Bo Jin,1 Kexin Lu,2 Wenna Gao,1 Yixian Liu,3 Mengfei Wang,2 Xiaojun Zhang,3 Huiping Chen,3 Liyun Zheng,3 Min Zou3 1Department of Ophthalmology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Hennan, 450052, People’s Republic of China; 2BGI College, Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 3Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, People’s Republic of ChinaCorrespondence: Min Zou; Liyun Zheng, Email Minzou1980@126.com; zhengliyun@zzu.edu.cnBackground: At present, the few photothermal/chemotherapy studies about retinoblastoma that have been reported are mainly restricted to ectopic models involving subcutaneous implantation. However, eyeball is unique physiological structure, the blood-retina barrier (BRB) hinders the absorption of drug molecules through the systemic route. Moreover, the abundant blood circulation in the fundus accelerates drug metabolism. To uphold the required drug concentration, patients must undergo frequent chemotherapy sessions.Purpose: To address these challenges above, we need to develop a secure and effective drug delivery system (FA-PEG-PDA-DOX) for the fundus.Methods: We offered superior therapeutic efficacy with minimal or no side effects and successfully established orthotopic mouse models. We evaluated cellular uptake performance and targeting efficiency of FA-PEG-PDA-DOX nanosystem and assessed its synergistic antitumor effects in vitro and vivo. Biodistribution assessments were performed to determine the retention time and targeting efficiency of the NPs in vivo. Additionally, safety assessments were conducted.Results: Cell endocytosis rates of the FA-PEG-PDA-DOX+Laser group became 5.23 times that of the DOX group and 2.28 times that of FA-PEG-PDA-DOX group without irradiation. The fluorescence signal of FA-PEG-PDA-DOX persisted for more than 120 hours at the tumor site. The number of tumor cells (17.2%) in the proliferative cycle decreased by 61.6% in the photothermal-chemotherapy group, in contrast to that of the saline control group (78.8%). FA-PEG-PDA-DOX nanoparticles(NPs) exhibited favorable biosafety and high biocompatibility.Conclusion: The dual functional targeted nanosystem, with the effects of DOX and mild-temperature elevation by irradiation, resulted in precise chemo/photothermal therapy in nude mice model.Keywords: retinoblastoma, orthotopic model, nanoparticle, synergistic therapy

Abstract Background Triple-negative breast cancer (TNBC) is a subtype of breast cancer with the worst prognosis. Radiotherapy (RT) is one of the core modalities for the disease; however, the ionizing radiation of RT has severe side effects. The consistent development direction of RT is to achieve better therapeutic effect with lower radiation dose. Studies have demonstrated that synergistic effects can be achieved by combining RT with non-ionizing radiation therapies such as light and magnetic therapy, thereby achieving the goal of dose reduction and efficacy enhancement. Methods In this study, we applied FeCo NPs with magneto thermal function and phototherapeutic agent IR-780 to construct an ionizing and non-ionizing radiation synergistic nanoparticle (INS NPs). INS NPs are first subjected to morphology, size, colloidal stability, loading capacity, and photothermal conversion tests. Subsequently, the cell inhibitory and cellular internalization were evaluated using cell lines in vitro. Following comprehensive assessment of the NPs’ in vivo biocompatibility, tumor-bearing mouse model was established to evaluate their distribution, targeted delivery, and anti-tumor effects in vivo. Results INS NPs have a saturation magnetization exceeding 72 emu/g, a hydrodynamic particle size of approximately 40 nm, a negatively charged surface, and good colloidal stability and encapsulation properties. INS NPs maintain the spectral characteristics of IR-780 at 808 nm. Under laser irradiation, the maximum temperature was 92 °C, INS NPs also achieved the effective heat temperature in vivo. Both in vivo and in vitro tests have proven that INS NPs have good biocompatibility. INS NPs remained effective for more than a week after one injection in vivo, and can also be guided and accumulated in tumors through permanent magnets. Later, the results exhibited that under low-dose RT and laser irradiation, the combined intervention group showed significant synergetic effects, and the ROS production rate was much higher than that of the RT and phototherapy-treated groups. In the mice model, 60% of the tumors were completely eradicated. Conclusions INS NPs effectively overcome many shortcomings of RT for TNBC and provide experimental basis for the development of novel clinical treatment methods for TNBC.

Abstract As an emerging cancer treatment strategy, reactive oxygen species-based tumor catalytic therapies face enormous challenges due to hypoxia and the overexpression of glutathione (GSH) in the tumor microenvironment. Herein, a self-assembled copper-based nanoplatform, TCCHA, was designed for enzyme-like catalysis-enhanced chemodynamic/photodynamic/antiangiogenic tritherapy against hepatocellular carcinoma. TCCHA was fabricated from Cu2+, 3,3′-dithiobis (propionohydrazide), and photosensitizer chlorine e6 via a facile one-pot self-assembly strategy, after which an aldehyde hyaluronic acid was coated, followed by loading of the antivascular drug AL3818. The obtained TCCHA nanoparticles exhibited pH/GSH dual-responsive drug release behaviors and multienzymatic activities, including Fenton, glutathione peroxidase-, and catalase-like activities. TCCHA, a redox homeostasis disruptor, promotes ⋅OH generation and GSH depletion, thus increasing the efficacy of chemodynamic therapy. TCCHA, which has catalase-like activity, can also reinforce the efficacy of photodynamic therapy by amplifying O2 production. In vivo, TCCHA efficiently inhibited tumor angiogenesis and suppressed tumor growth without apparent systemic toxicity. Overall, this study presents a facile strategy for the preparation of multienzyme-like nanoparticles, and TCCHA nanoparticles display great potential for enzyme catalysis-enhanced chemodynamic/photodynamic/antiangiogenic triple therapy against cancer. Graphical Abstract

Abstract Chemoresistance remains a significant challenge for effective breast cancer treatment which leads to cancer recurrence. CRISPR-directed gene editing becomes a powerful tool to reduce chemoresistance by reprogramming the tumor microenvironment. Previous research has revealed that Chinese herbal extracts have significant potential to overcome tumor chemoresistance. However, the therapeutic efficacy is often limited due to their poor tumor targeting and in vivo durability. Here we have developed a tumor microenvironment responsive nanoplatform (H-MnO2(ISL + DOX)-PTPN2@HA, M(I + D)PH) for nano-herb and CRISPR codelivery to reduce chemoresistance. Synergistic tumor inhibitory effects were achieved by the treatment of isoliquiritigenin (ISL) with doxorubicin (DOX), which were enhanced by CRISPR-based gene editing to target protein tyrosine phosphatase non-receptor type 2 (PTPN2) to initiate long-term immunotherapy. Efficient PTPN2 depletion was observed after treatment with M(I + D)PH nanoparticles, which resulted in the recruitment of intratumoral infiltrating lymphocytes and an increase of proinflammatory cytokines in the tumor tissue. Overall, our nanoparticle platform provides a diverse technique for accomplishing synergistic chemotherapy and immunotherapy, which offers an effective treatment alternative for malignant neoplasms. Graphical Abstract

Lingling Shan,1 Yudie Li,1 Yifan Ma,2 Yang Yang,1 Jing Wang,1 Lei Peng,1 Weiwei Wang,1 Fang Zhao,1 Wanrong Li,1 Xiaoyuan Chen3– 6 1Institute of Pharmaceutical Biotechnology, School of Biology and Food Engineering, Suzhou University, Suzhou, People’s Republic of China; 2Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, People’s Republic of China; 3Departments of Diagnostic Radiology, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, Singapore; 4Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; 5Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; 6Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), Singapore, SingaporeCorrespondence: Xiaoyuan Chen; Lingling Shan, Email chen.shawn@nus.edu.sg; ntlinger-300@163.comBackground: While nanoplatform-based cancer theranostics have been researched and investigated for many years, enhancing antitumor efficacy and reducing toxic side effects is still an essential problem.Methods: We exploited nanoparticle coordination between ferric (Fe2+) ions and telomerase-targeting hairpin DNA structures to encapsulate doxorubicin (DOX) and fabricated Fe2+-DNA@DOX nanoparticles (BDDF NPs). This work studied the NIR fluorescence imaging and pharmacokinetic studies targeting the ability and biodistribution of BDDF NPs. In vitro and vivo studies investigated the nano formula’s toxicity, imaging, and synergistic therapeutic effects.Results: The enhanced permeability and retention (EPR) effect and tumor targeting resulted in prolonged blood circulation times and high tumor accumulation. Significantly, BDDF NPs could reduce DOX-mediated cardiac toxicity by improving the antioxidation ability of cardiomyocytes based on the different telomerase activities and iron dependency in normal and tumor cells. The synergistic treatment efficacy is enhanced through Fe2+-mediated ferroptosis and the β-catenin/p53 pathway and improved the tumor inhibition rate.Conclusion: Harpin DNA-based nanoplatforms demonstrated prolonged blood circulation, tumor drug accumulation via telomerase-targeting, and synergistic therapy to improve antitumor drug efficacy. Our work sheds new light on nanomaterials for future synergistic chemotherapy. Keywords: DNA nanomaterials, targeting, imaging, synergistic therapy

Osteosarcoma (OS) is one of the most common malignant tumors in children and young adults. As chemotherapy and other therapies are limited by low therapeutic efficiency, severe side effects and single therapeutic function, it is of high value to develop innovative therapies for precise and efficient treatment of OS. Herein, natural photosynthetic microalgae (C. vulgaris, CV) were utilized as carriers for the chemotherapeutic agent doxorubicin (DOX) to create a multifunctional therapeutic platform (CV@DOX) for the photo-modulation of the tumor microenvironment (TME) and synergistic chemo-photodynamic therapy of osteosarcoma. CV@DOX exhibited rapid drug release behavior in the acidic TME, improving the efficiency of chemotherapy against tumors and reducing side effects on other normal tissues. Under 650 nm laser irradiation, CV@DOX demonstrated the ability to effectively generate oxygen to alleviate tumor hypoxia and utilize the photosensitizing properties of chlorophyll in CV to produce an increased amount of reactive oxygen species (ROS), thereby enhancing photodynamic therapy (PDT). CV@DOX-mediated synergistic chemo-photodynamic therapy demonstrated efficacy in halting tumor progression in an orthotopic osteosarcoma mouse model by promoting tumor cell apoptosis, inhibiting tumor proliferation and angiogenesis. Moreover, chlorophyll-assisted fluorescence imaging enabled monitoring of the distribution of CV@DOX in osteosarcoma after administration. Finally, CV@DOX did not cause significant hematological and tissue toxicity, and prevented DOX-induced cardiotoxicity, showing good in vivo biocompatibility. Overall, this work presents a novel TME-responsive and TME-modulating platform for imaging-guided multimodal osteosarcoma treatment.

Triple negative breast cancer (TNBC) represents a highly aggressive variant of breast cancer characterized by elevated rates of recurrence and mortality. Chemotherapy's application as a main cancer therapy is restricted due to its harmful side effects and resistance to medication. In this study, we utilized a covalent organic framework (COF) to apply indocyanine green (ICG), a photothermal agent, and gambogic acid (GA), an inhibitor of heat shock protein 90 (HSP90), to treat triple negative breast cancer. MTT results showed that the viability of tumor cells decreased more under laser irradiation conditions after the addition of GA than in the COF@ICG group. In addition, protein blotting results showed that under the action of GA, the blank group exhibited significantly higher HSP90 expression levels than the experimental group. The above results indicate that COF@ICG@GA enhances the therapeutic effect of PTT on cancer by inhibiting the expression of HSP90 in triple negative breast cancer cells and enhancing the sensitivity of tumor cells to temperature. [ABSTRACT FROM AUTHOR]

One of the most important issues in the design and preparation of drug delivery systems in the recent years is versatility which includes providing synergistic therapeutic effects and sustainability. This study uses a redox‐active ferrocenyl surfactant (FcN+(CH2CH3)3(CH2)10CH3, Fc(C11) where Fc is ferrocene) and pH responsive Zeolitic Imidazolate Framework‐8 (ZIF‐8) structures to form multifunctional assemblies (Fc(C11)‐AOT/Rhb@ZIF‐8/PDA) that can be used in several application including the drug delivery. The vesicles prepared using AOT‐FC(C11) constitute the core of the structure. Since the location of the ferrocene group in the molecule structure, which is next to head group, the surface of the vesicles is decorated with the ferrocene group which can act as a Fenton reaction catalyst. The polydopamine (PDA) covered ZIF‐8 are used to decorate the surface of the vesicles, creating a truly remarkable structure. The porous structure of ZIF‐8 as well as the core of the vesicles can accommodate drug molecules. With the added NIR‐responsive character upon PDA coating, this assembled structure can be used for phototermal therapy applications. The properties of this designed multifunctional and multi‐responsive system are studied at different pH and under NIR‐laser irradiation and show that it has potential to display a triple chemodynamic/ photothermal/ chemotherapeutic effect. [ABSTRACT FROM AUTHOR]

Introduction: Breast cancer is one of the most prevalent cancers, primarily affecting women. Among its subtypes, estrogen receptor-positive (ER+) breast cancer is particularly common. Inhibiting estrogen's effects is crucial for treating ER+ breast cancer, but current therapies often have significant side effects and limitations. Chrysin, a natural flavonoid, has shown potential in reducing estrogen receptor expression, but its poor water solubility hampers clinical application. This study explores the use of mesoporous dopamine nanoparticles (mPDA) to enhance the delivery and efficacy of Chrysin, combined with photothermal therapy (PTT), for breast cancer treatment. Methods: Chrysin-loaded mPDA nanoparticles (Chrysin@mPDA) were synthesized and characterized for their morphology, drug-loading efficiency, stability, and photothermal properties. Network pharmacology was used to predict Chrysin's mechanisms in breast cancer, which were validated through gene expression analysis in cell experiments. The therapeutic efficacy of Chrysin@mPDA with and without PTT was evaluated in a mouse model of breast cancer, with tumor volume and weight measured. Immunohistochemical analysis was conducted to assess estrogen receptor expression and immune cell infiltration in tumor tissues. Results: Chrysin@mPDA nanoparticles demonstrated a high drug-loading capacity and excellent stability. Photothermal studies confirmed the nanoparticles' ability to generate heat upon laser exposure, significantly enhancing Chrysin release in acidic conditions with laser irradiation. Network pharmacology identified key target genes affected by Chrysin, including ESR1, BRCA1, CTNNB1, and BAX, which were validated through qPCR. In vivo, the combination of Chrysin@mPDA and PTT significantly reduced tumor volume and weight, decreased estrogen receptor-positive cells, and increased infiltration of CD3+CD4+ and CD3+CD8+ T cells in tumor tissues. Discussion: The study highlights the potential of Chrysin-loaded mPDA nanoparticles combined with PTT as an effective strategy for breast cancer treatment. This approach addresses the limitations of Chrysin's solubility and enhances its therapeutic efficacy through synergistic mechanisms. The dual action of Chrysin in modulating gene expression and PTT in inducing localized hyperthermia and immune response suggests a promising avenue for improved breast cancer prognosis and reduced recurrence. [ABSTRACT FROM AUTHOR]

Chemodynamic therapy (CDT) alone cannot achieve sufficient therapeutic effects due to the excessive glutathione (GSH) and hypoxia in the tumor microenvironment (TME). Developing a novel strategy to improve efficiency is urgently needed. Herein, we prepared a copper silicate nanoplatform (CSNP) derived from colloidal silica. The Cu(II) in CSNP can be reduced to Cu(I), which cascades to induce a subsequent CDT process. Additionally, benefiting from GSH depletion and oxygen (O2) generation under 660 nm laser irradiation, CSNP exhibits both Fenton-like and hypoxia-alleviating activities, contributing to the effective generation of superoxide anion radical (•O2−) and hydroxyl radical (•OH) in the TME. Furthermore, given the suitable band-gap characteristic and excellent photochemical properties, CSNP can also serve as an efficient type-I photosensitizer for photodynamic therapy (PDT). The synergistic CDT/PDT activity of CSNP presents an efficient antitumor effect and biosecurity in both in vitro and in vivo experiments. The development of an all-in-one nanoplatform that integrates Fenton-like and photosensing properties could improve ROS production within tumors. This study highlights the potential of silicate nanomaterials in cancer treatment. [ABSTRACT FROM AUTHOR]

Four-component of double-layer infinite coordination polymer (ICP) nanocomposites were formulated. Lot of high efficiency synergies among four components have been identified, revealing combinations with remarkably low combination index (CI) values, forming a powerful electrothermal-thermodynamic-multi-chemo trimodal synergistic therapy for large tumors.This approach has an tumor inhibition rate of 100 % in 16 days and no tumor recurrence within 60 days. [Display omitted] Multimodal /components tumors synergistic therapy is a crucial approach for enhancing comprehensive efficacy. Our research has identified lots of high efficiency synergies among four suitable components, revealing combinations with remarkably low combination index (CI) values (10-3-10-8). These combinations hold promise for large tumor powerful electrothermal-thermodynamic-multi-chemo trimodal therapy. To implement this approach, we developed four-component of double-layer infinite coordination polymer (ICP) nanocomposites, in which hypoxia-activated AQ4N and thermodynamic agent AIPH coordinated with Cu(Ⅱ) to form initial layer of positively charged ICPs-l NPs, chemotherapeutic agents gossypol-hyaluronic acid (G-HA) and CA4 coordinated with Fe(Ⅲ) to form out layer of negatively charged ICPs-2 NPs, then double-layer infinite coordination polymer nanocomposites (ICPs-1@ICPs-2 CNPs) were fabricated by electrostatic adsorption using ICPs-l NPs and ICPs-2 NPs. Cell experiments have extensively optimized the coordination combinations of the four components and the composition of the two layers. A programmable three-stage therapeutic procedure, assisted by a micro-electrothermal needle (MEN), was developed. Under this procedure the resulting nanocomposites demonstrate the powerful trimodal comprehensive therapeutic outcomes for large tumors using lower components dosage, achieving a tumor inhibition rate nearly reaching 100 % and no recurrence for 60 days. This study offers remarkable potential for tumor multimodal /components synergistic therapy in future. [ABSTRACT FROM AUTHOR]

Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer with the worst prognosis. Radiotherapy (RT) is one of the core modalities for the disease; however, the ionizing radiation of RT has severe side effects. The consistent development direction of RT is to achieve better therapeutic effect with lower radiation dose. Studies have demonstrated that synergistic effects can be achieved by combining RT with non-ionizing radiation therapies such as light and magnetic therapy, thereby achieving the goal of dose reduction and efficacy enhancement. Methods: In this study, we applied FeCo NPs with magneto thermal function and phototherapeutic agent IR-780 to construct an ionizing and non-ionizing radiation synergistic nanoparticle (INS NPs). INS NPs are first subjected to morphology, size, colloidal stability, loading capacity, and photothermal conversion tests. Subsequently, the cell inhibitory and cellular internalization were evaluated using cell lines in vitro. Following comprehensive assessment of the NPs' in vivo biocompatibility, tumor-bearing mouse model was established to evaluate their distribution, targeted delivery, and anti-tumor effects in vivo. Results: INS NPs have a saturation magnetization exceeding 72 emu/g, a hydrodynamic particle size of approximately 40 nm, a negatively charged surface, and good colloidal stability and encapsulation properties. INS NPs maintain the spectral characteristics of IR-780 at 808 nm. Under laser irradiation, the maximum temperature was 92 °C, INS NPs also achieved the effective heat temperature in vivo. Both in vivo and in vitro tests have proven that INS NPs have good biocompatibility. INS NPs remained effective for more than a week after one injection in vivo, and can also be guided and accumulated in tumors through permanent magnets. Later, the results exhibited that under low-dose RT and laser irradiation, the combined intervention group showed significant synergetic effects, and the ROS production rate was much higher than that of the RT and phototherapy-treated groups. In the mice model, 60% of the tumors were completely eradicated. Conclusions: INS NPs effectively overcome many shortcomings of RT for TNBC and provide experimental basis for the development of novel clinical treatment methods for TNBC. [ABSTRACT FROM AUTHOR]

As an emerging cancer treatment strategy, reactive oxygen species-based tumor catalytic therapies face enormous challenges due to hypoxia and the overexpression of glutathione (GSH) in the tumor microenvironment. Herein, a self-assembled copper-based nanoplatform, TCCHA, was designed for enzyme-like catalysis-enhanced chemodynamic/photodynamic/antiangiogenic tritherapy against hepatocellular carcinoma. TCCHA was fabricated from Cu2+, 3,3′-dithiobis (propionohydrazide), and photosensitizer chlorine e6 via a facile one-pot self-assembly strategy, after which an aldehyde hyaluronic acid was coated, followed by loading of the antivascular drug AL3818. The obtained TCCHA nanoparticles exhibited pH/GSH dual-responsive drug release behaviors and multienzymatic activities, including Fenton, glutathione peroxidase-, and catalase-like activities. TCCHA, a redox homeostasis disruptor, promotes ⋅OH generation and GSH depletion, thus increasing the efficacy of chemodynamic therapy. TCCHA, which has catalase-like activity, can also reinforce the efficacy of photodynamic therapy by amplifying O2 production. In vivo, TCCHA efficiently inhibited tumor angiogenesis and suppressed tumor growth without apparent systemic toxicity. Overall, this study presents a facile strategy for the preparation of multienzyme-like nanoparticles, and TCCHA nanoparticles display great potential for enzyme catalysis-enhanced chemodynamic/photodynamic/antiangiogenic triple therapy against cancer. [ABSTRACT FROM AUTHOR]

The blood brain barrier (BBB) limits the application of most therapeutic drugs for neurological diseases (NDs). Hybrid cell membrane‐coated nanoparticles derived from different cell types can mimic the surface properties and functionalities of the source cells, further enhancing their targeting precision and therapeutic efficacy. Neuroinflammation has been increasingly recognized as a critical factor in the pathogenesis of various NDs, especially Alzheimer's disease (AD). In this study, a novel cell membrane coating is designed by hybridizing the membrane from platelets and chemokine (C–C motif) receptor 2 (CCR2) cells are overexpressed to cross the BBB and target neuroinflammatory lesions. Past unsuccessful endeavors in AD drug development underscore the challenge of achieving favorable outcomes when utilizing single‐mechanism drugs.Two drugs with different mechanisms of actions into liposomes are successfully loaded to realize multitargeting treatment. In a transgenic mouse model for familial AD (5xFAD), the administration of these drug‐loaded hybrid cell membrane liposomes results in a significant reduction in amyloid plaque deposition, neuroinflammation, and cognitive impairments. Collectively, the hybrid cell membrane‐coated nanomaterials offer new opportunities for precise drug delivery and disease‐specific targeting, which represent a versatile platform for targeted therapy in AD. [ABSTRACT FROM AUTHOR]

Chemoresistance remains a significant challenge for effective breast cancer treatment which leads to cancer recurrence. CRISPR-directed gene editing becomes a powerful tool to reduce chemoresistance by reprogramming the tumor microenvironment. Previous research has revealed that Chinese herbal extracts have significant potential to overcome tumor chemoresistance. However, the therapeutic efficacy is often limited due to their poor tumor targeting and in vivo durability. Here we have developed a tumor microenvironment responsive nanoplatform (H-MnO2(ISL + DOX)-PTPN2@HA, M(I + D)PH) for nano-herb and CRISPR codelivery to reduce chemoresistance. Synergistic tumor inhibitory effects were achieved by the treatment of isoliquiritigenin (ISL) with doxorubicin (DOX), which were enhanced by CRISPR-based gene editing to target protein tyrosine phosphatase non-receptor type 2 (PTPN2) to initiate long-term immunotherapy. Efficient PTPN2 depletion was observed after treatment with M(I + D)PH nanoparticles, which resulted in the recruitment of intratumoral infiltrating lymphocytes and an increase of proinflammatory cytokines in the tumor tissue. Overall, our nanoparticle platform provides a diverse technique for accomplishing synergistic chemotherapy and immunotherapy, which offers an effective treatment alternative for malignant neoplasms. [ABSTRACT FROM AUTHOR]

Migration is an initial step in tumor expansion and metastasis; suppressing cellular migration is beneficial to cancer therapy. Herein, we designed a novel biogated nanoagents that integrated the migration inhibitory factor into the mesoporous silica nanoparticle (MSN) drug delivery nanosystem to realize cell migratory inhibition and synergistic treatment. Antisense oligonucleotides (Anti) of microRNA-330-3p, which is positively related with cancer cell proliferation, migration, invasion, and angiogenesis, not only acted as the locker for blocking drugs but also acted as the inhibitory factor for suppressing migration via gene therapy. Synergistic with gene therapy, the biogated nanoagents (termed as MSNs-Gef-Anti) could achieve on-demand drug release based on the intracellular stimulus-recognition and effectively kill tumor cells. Experimental results synchronously demonstrated that the migration suppression ability of MSNs-Gef-Anti nanoagents (nearly 30%) significantly contributed to cancer therapy, and the lethality rate of the non-small-cell lung cancer was up to 70%. This strategy opens avenues for realizing efficacious cancer therapy and should provide an innovative way for pursuing the rational design of advanced nano-therapeutic platforms with the combination of cancer cell migratory inhibition. [ABSTRACT FROM AUTHOR]

Although nanomaterial-based nanomedicine provides many powerful tools to treat cancer, most focus on the "immunosilent" apoptosis process. In contrast, ferroptosis and immunogenic cell death, two non-apoptotic forms of programmed cell death (PCD), have been shown to enhance or alter the activity of the immune system. Therefore, there is a need to design and develop nanoplatforms that can induce multiple modes of cell death other than apoptosis to stimulate antitumor immunity and remodel the immunosuppressive tumor microenvironment for cancer therapy. In this study, a new type of multifunctional nanocomposite mainly consisting of HMME, Fe3+ and Tannic acid, denoted HFT NPs, was designed and synthesized to induce multiple modes of cell death and prime the tumor microenvironment (TME). The HFT NPs consolidate two functions into one nano-system: HMME as a sonosensitizer for the generation of reactive oxygen species (ROS) 1O 2 upon ultrasound irradiation, and Fe3+ as a GSH scavenger for the induction of ferroptosis and the production of ROS ·OH through inorganic catalytic reactions. The administration of HFT NPs and subsequent ultrasound treatment caused cell death through the consumption of GSH, the generation of ROS, ultimately inducing apoptosis, ferroptosis, and immunogenic cell death (ICD). More importantly, the combination of HFT NPs and ultrasound irradiation could reshape the TME and recruit more T cell infiltration, and its combination with immune checkpoint blockade anti-PD-1 antibody could eradicate tumors with low immunogenicity and a cold TME. This new nano-system integrates sonodynamic and chemodynamic properties to achieve outstanding therapeutic outcomes when combined with immunotherapy. Collectively, this study demonstrates that it is possible to potentiate cancer immunotherapy through the rational and innovative design of relatively simple materials. Herein, we developed a novel nanoplatform capable of inducing various modes of cell death to stimulate antitumor immunity and remodel the immunosuppressive tumor microenvironment. Briefly, we designed and synthesized a new type of multifunctional nanoplatform, HFT NPs, which consolidate two functions into one nano-system: HMME as a sonosensitizer for the generation of reactive oxygen species (ROS) 1O 2 upon ultrasound irradiation and Fe3+ as a GSH scavenger for the induction of ferroptosis and the production of ROS (·OH) through inorganic catalytic reaction. The data from in vitro and in vivo studies demonstrate that the HFT NPs administration and local ultrasound irradiation induce the occurrence of apoptosis, ferroptosis, and immunogenic cell death (ICD), and inhibit tumor growth in vivo. Notably, the combination of HFT NP treatment with immune checkpoint inhibitors, such as anti-PD-1 antibody, resulted in remarkable anticancer activity, effectively halting tumor growth. [Display omitted] [ABSTRACT FROM AUTHOR]

Colorectal carcinoma (CRC) has become one of the most prevalent malignant tumors and exploring a potential therapeutic strategy with diminished drug-associated adverse effects to combat CRC is urgent. Herein, we designed a pH-responsive polymer to efficiently encapsulate a stimulator of interferon genes (STING) agonist (5,6- dimethylxanthenone-4-acetic acid, termed ASA404) and a common clinically used chemotherapeutic agent (1-hexylcarbamoyl-5-fluorouracil, termed HCFU). Investigations in vitro demonstrated that polymer encapsulation endowed the system with a pH-dependent disassembly behavior (pH t 6.37), which preferentially selected cancerous cells with a favorable dose reduction (dose reduction index (DRI) of HCFU was 4.09). Moreover, the growth of CRC in tumor-bearing mice was effectively suppressed, with tumor suppression rates up to 94.74%, and a combination index (CI) value of less than one (CI = 0.41 for CT26 cell lines), indicating a significant synergistic therapeutic effect. Histological analysis of the tumor micro-vessel density and enzyme-linked immunosorbent assay (ELISA) tests indicated that the system increased TNF-α and IFN-β levels in serum. Therefore, this research introduces a pH-responsive polymer-based theranostic platform with great potential for immune-chemotherapeutic and anti-vascular combination therapy of CRC. [Display omitted] [ABSTRACT FROM AUTHOR]

Sonodynamic therapy (SDT), utilizing ultrasound (US) as the trigger, has gained popularity recently as a therapeutic approach with significant potential for treating various diseases. Metal–organic frameworks (MOFs), characterized by structural flexibility, are prominently emerging in the SDT realm as an innovative type of sonosensitizer, offering functional tunability and biocompatibility. However, due to the inherent limitations of MOFs, such as low reactivity to reactive oxygen species and challenges posed by the complex tumor microenvironment, MOF-based sonosensitizers with singular functions are unable to demonstrate the desired therapeutic efficacy and may pose risks of toxicity, limiting their biological applications to superficial tissues. MOFs generally possess distinctive crystalline structures and properties, and their controlled coordination environments provide a flexible platform for exploring structure-effect relationships and guiding the design and development of MOF-based nanomaterials to unlock their broader potential in biological fields. The primary focus of this paper is to summarize cases involving the modification of different MOF materials and the innovative strategies developed for various complex conditions. The paper outlines the diverse application areas of functionalized MOF-based sonosensitizers in tumor synergistic therapies, highlighting the extensive prospects of SDT. Additionally, challenges confronting SDT are briefly summarized to stimulate increased scientific interest in the practical application of MOFs and the successful clinical translation of SDT. Through these discussions, we strive to foster advancements that lead to early-stage clinical benefits for patients. 1. An overview for the progresses in SDT explored from a novel and fundamental perspective. 2. Different modification strategies to improve the MOFs-mediated SDT efficacy are provided. 3. Guidelines for the design of multifunctional MOFs-based sonosensitizers are offered. 4. Powerful tumor ablation potential is reflected in SDT-led synergistic therapies. 5. Future challenges in the field of MOFs-based SDT in clinical translation are suggested. [Display omitted] [ABSTRACT FROM AUTHOR]

Ferroptosis induced by lipid peroxide (LPO) accumulation is an effective cell death pathway for cancer therapy. However, how to effectively induce ferroptosis at tumor sites and improve its therapeutic effectiveness remains challenging. Here, MnFe 2 O 4 @NaGdF 4 @NLG919@HA (MGNH) nanocomplex with tumor-specific targeting and TME response is constructed to overcome immunosuppressive tumor microenvironment (TME) to potentiate the curative effect of ferroptosis by coupling the immune checkpoint indoleamine 2,3-dioxygenase (IDO) inhibitor, NLG919, and hyaluronic acid (HA) to novel ultra-small MnFe 2 O 4 @NaGdF 4 (MG) nanoparticles with a Janus structure. Firstly, tumor site-precise delivery of MG and NLG919 is achieved with HA targeting. Secondly, MG acts as a magnetic resonance imaging contrast agent, which not only has a good photothermal effect to realize tumor photothermal therapy, but also depletes glutathione and catalyzes the production of reactive oxygen species from endogenous H 2 O 2 , which effectively promotes the accumulation of LPO and inhibits the expression of glutathione peroxidase 4, achieving enhanced ferroptosis. Thirdly, NLG919 inhibits the differentiation of Tregs by blocking the tryptophan/kynurenine immune escape pathway, thereby reversing immunosuppressive TME together with the Mn2+-activated cGAS-STING pathway. This work contributes new perspectives for the development of novel ultra-small Janus nanoparticles to reshape immunosuppressive TME and ferroptosis activation. The Janus structured MnFe 2 O 4 @NaGdF 4 @NLG919@HA (MGNH) nanocomplex was synthesized, which can realize the precise delivery of T1/T2 contrast agents MnFe 2 O 4 @NaGdF 4 (MG) and NLG919 at the tumor site under the ultra-small Janus structural characteristics and targeted molecule HA. The production of ROS, consumption of GSH, and photothermal properties of MGNH make it possible for CDT/PTT activated ferroptosis, and synergistically disrupt and reprogram tumor growth and immunosuppressive tumor microenvironment with NLG919 and Mn2+-mediated activation of cGAS-STING pathway, achieving CDT/PTT/immunotherapy activated by ferroptosis. Meanwhile, ultra-small structural properties of MGNH facilitate subsequent metabolic clearance by the body, allowing for the minimization of potential biotoxicity associated with its prolonged retention. [Display omitted] [ABSTRACT FROM AUTHOR]

A facilely topochemical-like reduction method is used to prepare narrow bandgap bismuth thiooxide and use it for tumor phototherapy under near-infrared light. [Display omitted] The physical property tuning of nanomaterials is of great importance in energy, medicine, environment, catalysis, and other fields. Topochemical synthesis of nanomaterials can achieve precise control of material properties. Here, we synthesized a kind of element-doped bismuth-based nanomaterial (BOS) by topochemical-like synthesis and used it for the phototherapy of tumors. In this study, we employed bismuth fluoride nanoflowers as a template and fabricated element-doped bismuth oxide nanoflowers by reduction conditions. The product is consistent with the precursor in crystal structure and nanomorphology, realizing topochemical-like synthesis under mild conditions. BOS can generate reactive oxygen species, consume glutathione, and perform photothermal conversion under 730 nm light irradiation. In vitro and in vivo studies demonstrate that BOS could suppress tumor growth by inducing apoptosis and ferroptosis through phototherapy. Therefore, this study offers a general regulation method for tuning the physical properties of nanomaterials by using a topochemical-like synthesis strategy. [ABSTRACT FROM AUTHOR]

Bacterial infectious diseases seriously threaten global public health. The inappropriate use of antibiotics promoted the emergence and widespread of drug-resistant bacteria; thus, nanomaterial-based antibacterial agents are considered promising alternatives to combat bacterial infections. Herein, a near-infrared (NIR) light and hydrogen peroxide (H2O2) dually triggered halloysite nanotube (HNT)-based nanoplatform (HNTs@PDA/PB) as a broad-spectrum antibacterial agent was fabricated via a facile two-step strategy. Specifically, as natural clay materials, HNTs were first coated with a versatile layer of polydopamine (PDA). Then, the catechol groups on the PDA surface served as a chelating and reducing agent, facilitating the in situ growth of Prussian blue (PB) nanoparticles. The as-prepared HNTs@PDA/PB exhibited strong absorption in the NIR region and peroxidase-like activity, which suggested that it can act as a photothermal and Fenton dual-modal agent. Under NIR irradiation and exogenous H2O2, HNTs@PDA/PB exhibited excellent bactericidal activity via photothermal-enhanced chemodynamic therapy against multiple pathogenic bacteria, eliminating 68.0 ± 0.4% of the Staphylococcus aureus biofilm and 61.6 ± 0.3% of the methicillin-resistant S. aureus (MRSA) biofilm. In vivo studies further demonstrated that HNTs@PDA/PB could achieve efficient bacterial eradication and accelerate wound healing. Overall, this versatile HNT-based nanoplatform can serve as a promising therapeutic candidate to fight against bacterial infectious diseases. [ABSTRACT FROM AUTHOR]

5-Fluorouracil (5FU) and its derivatives have been widely used for cancer treatment; however they fail to achieve selective chemotherapy. Herein, this work highlights a successful development of a pH-sensitive aliphatic 5-fluorouracil (5FU) derivative prodrug, which is synthesized via chemically linking 5FU and stearyl alcohol (SA) using ortho ester linkage. It can further self-assemble into a synergistic small molecule nanodrug through a noncovalent interaction with doxorubicin (DOX). The nanodrug displays precise structure and high drug loading (more than 15% of drug loading content (DLC) and 87% of drug loading efficiency (DLE)). SA and ortho ester linkages endow the nanodrug with high lipophilicity on tumor cell membrane and tumoral intracellular pH response, respectively. The nanodrug also exhibits a slightly negatively charged surface (−0.513 mV) at physiological pH (7.4) and a large-to-small size change from 176.2 to 128.9 nm at tumoral intracellular pH (5.0). These superior characteristics endow the nanodrugs with blood circulation stability, selective tumor accumulation, improved cellular uptake, efficient drug release, as well as synergistic effect on tumor cells, thereby significantly inhibiting tumor growth (smaller than initial tumor size), reducing side effects, and prolonging survival time. Thus, such a pH-sensitive small molecule nanodrug self-assembled from the aliphatic 5FU derivative and DOX has a great potential for selective synergistic cancer therapy, greatly advancing their clinical use. [ABSTRACT FROM AUTHOR]

Thrombus has long been the major contributor of death and disability because it can cause adverse effects to varying degrees on the body, resulting in vascular blockage, embolism, heart valve deformation, widespread bleeding, etc. However, clinically, conventional thrombolytic drug treatments have hemorrhagic complication risks and easy to miss the best time of treatment window. Thus, it is an urgent need to investigate newly alternative treatment strategies that can reduce adverse effects and improve treatment effectiveness. Drugs based on nanomaterials act as a new biomedical strategy and promising tools, and have already been investigated for both diagnostic and therapeutic purposes in thrombus therapy. Recent studies have some encouraging progress. In the present review, we primarily concern with the latest developments in the areas of nanomedicines targeting thrombosis therapy. We present the thrombus' formation, characteristics, and biomarkers for diagnosis, overview recent emerging nanomedicine strategies for thrombus therapy, and focus on the future design directions, challenges, and prospects in the nanomedicine application in thrombus therapy. [ABSTRACT FROM AUTHOR]

Abstract PD‐1/PD‐L1 inhibitors have emerged as standard treatments for advanced solid tumors; however, challenges such as a low overall response rate and systemic side effects impede their implementation. Hypoxia drives the remodeling of the tumor microenvironment, which is a leading reason for the failure of immunotherapies. Despite some reported strategies to alleviate hypoxia, their individual limitations constrain further improvements. Herein, a novel two‐pronged strategy is presented to efficiently address hypoxia by simultaneously adopting atovaquone (ATO, inhibiting oxygen consumption) and oxyhemoglobin (HbO2, directly supplementing oxygen) within a multifunctional aggregate termed NPs‐aPD‐1/HbO2/ATO. In addition to eliminating hypoxia with these two components, this smart aggregate also includes albumin and an ROS‐responsive cross‐linker as a controlled release scaffold, along with PD‐1 antibody (aPD‐1) for immunotherapy. Intriguingly, NPs‐aPD‐1/HbO2/ATO demonstrates exceptional tumor targeting in vivo, exhibiting ≈4.2 fold higher accumulation in tumors than in the liver. Consequently, this aggregate not only effectively mitigates hypoxia and significantly assists aPD‐1 immunotherapy but also simultaneously resolves the targeting and systemic toxicity issues associated with individual administration of each component. This study proposes substantial implications for drug‐targeted delivery, addressing tumor hypoxia and advancing immunotherapy, providing valuable insights for advancing cancer treatment strategies.

Nanomedicine‐induced cancer cell death has become a prominent area of research in the life sciences field in recent years. The concept of cuproptosis was first proposed in 2022. Copper homeostasis in organisms is tightly regulated by protein transporters and molecular chaperones. Disruptions in copper homeostasis can adversely affect mitochondrial respiration and disrupt other physiological processes, leading to cytotoxicity. Therefore, researchers have designed and refined copper‐based nanomaterials to induce cuproptosis and assess their effects on cancer treatment. While several reviews on cuproptosis exist, they primarily delve into its molecular mechanisms. This review begins with elucidating the metabolism and homeostasis of copper in the body. Subsequently, the latest advancements in copper nanomaterial‐induced cuproptosis for cancer treatment and antimicrobial purposes is summarized. Finally, a comprehensive summary and outlook on the subject is provided. The goal with this review is to assist researchers in gaining a deeper understanding of the interaction between nanomaterials and cuproptosis, thereby offering new perspectives for designing novel nanomaterials to induce cuproptosis.

Abstract Background Osteoporosis is characterized by an imbalance in bone homeostasis, resulting in the excessive dissolution of bone minerals due to the acidified microenvironment mediated by overactive osteoclasts. Oroxylin A (ORO), a natural flavonoid, has shown potential in reversing osteoporosis by inhibiting osteoclast-mediated bone resorption. The limited water solubility and lack of targeting specificity hinder the effective accumulation of Oroxylin A within the pathological environment of osteoporosis. Results Osteoclasts’ microenvironment-responsive nanoparticles are prepared by incorporating Oroxylin A with amorphous calcium carbonate (ACC) and coated with glutamic acid hexapeptide-modified phospholipids, aiming at reinforcing the drug delivery efficiency as well as therapeutic effect. The obtained smart nanoparticles, coined as OAPLG, could instantly neutralize acid and release Oroxylin A in the extracellular microenvironment of osteoclasts. The combination of Oroxylin A and ACC synergistically inhibits osteoclast formation and activity, leading to a significant reversal of systemic bone loss in the ovariectomized mice model. Conclusion The work highlights an intelligent nanoplatform based on ACC for spatiotemporally controlled release of lipophilic drugs, and illustrates prominent therapeutic promise against osteoporosis.

Androgenetic alopecia (AGA) is a common clinical condition, affecting over 200 million people globally each year. For decades, Minoxidil (Mi) tincture has been the primary treatment for this disease, but its low utilization rate and significant side effects necessitate new therapeutic strategies. Nitric oxide (NO) is a signaling molecule in various physiological processes, including vasodilation, immune responses, and cell proliferation. Herein, we constructed a hyaluronic acid liposome (HL) complex as a novel transdermal delivery system (HL@Mi/NONOate) for NO and Mi, which displayed promising transdermal and hair-regrowth effects. In-depth mechanistic studies revealed three potential pathways of the synergistic AGA therapy. First, NO promoted capillary dilation and accelerated blood flow, thus achieving efficient penetration of Mi. Due to the structural advantage of liposomes, the residence time of the Mi in the skin was prolonged. Moreover, HL@Mi/NONOate promoted cell proliferation and angiogenesis, and upregulated the expression of regulatory factors involved in follicle stem cell differentiation. In the AGA model, HL@Mi/NONOate down-regulated the expression of inflammatory factors, inhibiting the inflammation of follicle and improving the microenvironment of hair regrowth. Concurrently, HL@Mi/NONOate upregulated the expression of Ki67 and PCNA proteins in follicle tissues, inducing follicle regeneration and development, ultimately achieving the synergistic multimodal AGA therapy.

Chemodynamic therapy (CDT) generating hydroxyl radicals (•OH) by utilizing metal ions reacting with hydrogen peroxide (H2O2) is a highly encouraging strategy for cancer treatment. However, highly expressed GSH in tumor cells severely limits the efficacy of CDT, and CDT alone is also not sufficient to produce excellent antitumor efficiency. Herein, a dual GSH depletion nanosystem (MnO2@PDA@PEG@DOX) was designed and synthesized to achieve synergistic cancer treatment under ultrasound (US) irritation. To achieve an acidic response, dopamine (DA) was loaded onto manganese dioxide, and the water solubility and stability were greatly improved after PEG modification; finally, the loading of doxorubicin (DOX) achieved the combinational therapy. When the nanoparticles arrived at the tumor site, the acidic and high expression of GSH in the tumor microenvironment prompted the degrading of the nanosystem, followed by the release of MnO2 and DOX. The released MnO2 can react with intracellular GSH to produce Mn2+, which realizes chemodynamic therapy by catalyzing H2O2 to generate highly toxic hydroxyl radicals (•OH) at the tumor site; also, the depletion of GSH will significantly promote the level of •OH, improving the efficiency of CDT simultaneously. Moreover, the release of DOX could be boosted by US irradiation, thus enhancing the effect of chemotherapy on DOX and achieving sonodynamic therapy (SDT). Therefore, strategies to enhance CDT efficiency by dual GSH depletion and combining chemotherapy and sonodynamic therapy modalities can provide more ideas and approaches for combination therapy in cancer treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel Au NBPs@Pt NCs-ICG nanozyme was constructed with Au nanobipyrimds, Pt nanoclusters and ICG. • The Au NBPs@Pt NCs-ICG nanozyme exhibited excellent multienzymatic activity for effective TME modulation and ROS generation. • The FL/CT/PTI trimodal imaging of the nanocomposites were successfully applied. • Synergistic photothermal, photodynamic and chemodynamic cancer therapy was realized on 4T1 tumor-bearing mice model. Synergistic therapy is expected to be a promising strategy for highly effective cancer treatment. However, the rational design of a simple and multifunctional nanoplatform still remains a grand challenge. Considering the nature of weak acidic, hypoxic, and H 2 O 2 abundant tumor microenvironment, we constructed an indocyanine green (ICG) modified platinum nanoclusters (Pt NCs) decorated gold nanobipyramids (Au NBPs) to form the multifunctional nanocomposites (Au NBPs@Pt NCs-ICG) for multimodal imaging mediated phototherapy and chemodynamic cancer therapy. The photosensitizer ICG was covalently linked to Au NBPs@Pt NCs by bridging molecules of SH-PEG-NH 2 for both photodynamic therapy (PDT) and fluorescence imaging. Besides, Au NBPs@Pt NCs-ICG nanocomposites exhibited catalase- and peroxidase-like activities to generate O 2 and ·OH, which relieved the tumor hypoxia and upregulated antitumoral ROS level. Moreover, the combination of Au NBPs and ICG endowed the Au NBPs@Pt NCs-ICG with super photothermal conversion for effective photothermal imaging and therapy. In addition, the Au NBPs@Pt NCs-ICG nanoplatform displayed excellent X-ray computed tomography (CT) imaging ability due to the presence of high-Z elements (Au and Pt). Overall, our results demonstrated that Au NBPs@Pt NCs-ICG nanoplatform exhibited a multimodal imaging guided synergistic PTT/PDT/CDT therapeutic manners and held great potential as an efficient treatment for breast cancer. [ABSTRACT FROM AUTHOR]

How to boost the therapeutic efficiency is still the key to translation of anticancer nanomedicine from preclinical investigations to clinical practice. In this work, we proposed to integrate 211At-derived targeted-alpha therapy (TAT) and photothermal therapy (PTT) into nanoscale polydopamine (PDA), attempting to obtain a feasible solution to circumvent the barriers both in 211At-based endoradiotherapy and common nanomedicine. After radiolabeling with 211At and fibroblast activation protein inhibitor (FAPI) decoration of PDA nanoparticles, the obtained 211At-PDA-FAPI exhibits considerable photothermal conversion efficiency, high radioactive stability, excellent cancer affinity, and remarkable antitumor ability. The synergistic TAT-PTT therapeutic effect of 211At-PDA-FAPI in murine xenograft models of glioma has been well confirmed, with the tumor growth inhibition values of 80.82, 76.70, and 96.71% at 15 days postinjection for PTT, TAT, and TAT-PTT treatments, respectively. Meanwhile, the TAT-PTT regimen can prolong the median survival of tumor-bearing mice two times from 18 to 36 days, without detectable biotoxicity during the whole treatment. The outcome of this work provides important hints for the design of therapeutic nanomedicine and the development of traditional radiopharmaceuticals. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis is characterized by an imbalance in bone homeostasis, resulting in the excessive dissolution of bone minerals due to the acidified microenvironment mediated by overactive osteoclasts. Oroxylin A (ORO), a natural flavonoid, has shown potential in reversing osteoporosis by inhibiting osteoclast-mediated bone resorption. The limited water solubility and lack of targeting specificity hinder the effective accumulation of Oroxylin A within the pathological environment of osteoporosis. Results: Osteoclasts' microenvironment-responsive nanoparticles are prepared by incorporating Oroxylin A with amorphous calcium carbonate (ACC) and coated with glutamic acid hexapeptide-modified phospholipids, aiming at reinforcing the drug delivery efficiency as well as therapeutic effect. The obtained smart nanoparticles, coined as OAPLG, could instantly neutralize acid and release Oroxylin A in the extracellular microenvironment of osteoclasts. The combination of Oroxylin A and ACC synergistically inhibits osteoclast formation and activity, leading to a significant reversal of systemic bone loss in the ovariectomized mice model. Conclusion: The work highlights an intelligent nanoplatform based on ACC for spatiotemporally controlled release of lipophilic drugs, and illustrates prominent therapeutic promise against osteoporosis. [ABSTRACT FROM AUTHOR]

Cancer has been the most deadly disease, and 13 million cancer casualties are estimated to occur each year by 2030. Gold nanoparticles (AuNPs)‐based photothermal therapy (PTT) has attracted great interest due to its high spatiotemporal controllability and noninvasiveness. Due to the trade‐off between particle size and photothermal efficiency of AuNPs, rational design is needed to realize aggregation of AuNPs into larger particles with desirable NIR adsorption in tumor site. Exploiting the bioorthogonal "Click and Release" (BCR) reaction between iminosydnone and cycloalkyne, aggregation of AuNPs can be achieved and attractively accompanied by the release of chemotherapeutic drug purposed to photothermal synergizing. We synthesize iminosydnone‐lonidamine (ImLND) as a prodrug and choose dibenzocyclooctyne (DBCO) as the trigger of BCR reaction. A PEGylated AuNPs‐based two‐component nanoplatform consisting of prodrug‐loaded AuNPs‐ImLND and tumor‐targeting peptide RGD‐conjugated AuNPs‐DBCO‐RGD is designed. In the therapeutic regimen, AuNPs‐DBCO‐RGD are intravenously injected first for tumor‐specific enrichment and retention. Once the arrival of AuNPs‐ImLND injected later at tumor site, highly photothermally active nanoaggregates of AuNPs are formed via the BCR reaction between ImLND and DBCO. The simultaneous release of lonidamine further enhanced the therapeutic performance by sensitizing cancer cells to PTT. [ABSTRACT FROM AUTHOR]