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[Display omitted] Chemodynamic therapy (CDT) and photothermal therapy (PTT) have both demonstrated considerable efficacy in the tumor treatment individually, owing to their non-invasive nature and excellent selectivity. However, due to the propensity of tumors for metastasis and recurrence, a singular therapeutic approach falls short of achieving optimal treatment outcomes. Polydopamine (PDA) has excellent photothermal conversion ability and polyoxometalates (POMs) possess diverse enzymatic activities. Here, we synthesized PDA@POM nanospheres comprising polydopamine-coated Tungsten-based polyoxometalate (W-POM). These nanospheres leverage dual enzymatic activities that synergistically enhance both chemodynamic and photothermal therapies for tumor treatment. The PDA-mediated PTT effect enables precise tumor cell destruction, while the W-POM nanozymes catalyzes the generation of highly toxic reactive oxygen species (ROS) from hydrogen peroxide within tumor cells through a Fenton-like reaction, which mitigates tumor hypoxia and induces tumor cell death. This synergistic photothermal catalytic therapy shows enhanced efficacy in tumor suppression, providing a promising new approach for tumor treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] The combination of chemodynamic therapy (CDT) with photothermal therapy (PTT) is a promising approach to enhance antitumor efficacy of chemotherapeutics. In this paper, we developed novel copper-chelated polydopamine (PDA) nanoparticles (NPs) functionalized with hyaluronic acid (HA) (Cu-PDA-HA NPs) to induce apoptosis and cuproptosis-induced cell death, synergistically combining PTT and CDT. Experimental results revealed that Cu-PDA-HA NPs can respond to excessive glutathione (GSH) and hydrogen peroxide (H 2 O 2) in the tumor microenvironment (TME), which will enable their specific degradation, thereby leading to efficient accumulation of Cu2+ within tumor cells. The released Cu2+ ions were reduced by GSH to generate Cu+, which catalyzed in situ Fenton-like reactions to produce cytotoxic hydroxyl radicals (·OH), disrupting cellular redox homeostasis and promoting apoptosis-related CDT. Meanwhile, the photothermal effect of the Cu-PDA-HA NPs could enhance oxidative stress within the tumor by elevating the temperature and subsequent ·OH production. The enhanced oxidative stress made tumor cells more vulnerable to cuproptosis-induced toxicity. Furthermore, in vivo experiments demonstrated that Cu-PDA-HA NPs can still undergo a temperature increase of 18.9°C following 808 nm near-infrared irradiation (1.0 W/cm2, 5 min). Meanwhile, Cu-PDA-HA NPs were able to induce oligomerization of dihydrolipoamide S-acetyltransferase (DLAT) and down-regulate Fe-S cluster proteins such as ferredoxin (FDX1), thereby activating cuproptosis. Therefore, this study provides a novel approach for designing multifunctional nanoparticles with on-demand Cu2+ release and offers a fresh perspective for exploring synergistic therapeutic strategies involving CDT/PTT/apoptosis/cuproptosis. [ABSTRACT FROM AUTHOR]

Chronic wounds, particularly those associated with diabetes, pose a significant clinical challenge due to their tendency to develop biofilms that resist conventional antibiotic treatments. To address this issue, a novel therapeutic strategy utilizing pH‐responsive nanoparticles loaded with aggregation‐induced emission photosensitizers and natural saturated fatty acids (AIE/LA@HMONs−PyB) for effective biofilm penetration and disruption is proposed. Under physiological conditions, AIE/LA@HMONs−PyB are negatively charged. Upon accumulation at infected sites, however, the pyridine betaine group on the surface of AIE/LA@HMONs−PyB enables rapid protonation and charge reversal in the acidic biofilm microenvironment, thereby enhancing their ability to penetrate the biofilm. Upon light irradiation, these nanoparticles generate reactive oxygen species that effectively disrupt the biofilm structure. This process enables the synergistic action of ciprofloxacin at a lower concentration, achieving an exceptional in vitro antibacterial efficiency of 99.99% against methicillin‐resistant Staphylococcus aureus (S. aureus) biofilms. Furthermore, in an in vivo diabetic wound model, this synergistic therapy accelerates wound healing by reducing inflammation, promoting angiogenesis, and enhancing collagen regeneration. The enhanced penetration strategy significantly improves the therapeutic efficacy of this combined approach, offering great promise for advancing chronic wound healing and enhancing patient outcomes. [ABSTRACT FROM AUTHOR]

Tumor heterogeneity, immune-suppressive microenvironment and the precise killing of tumor cells by drugs are important factors affecting tumor treatment. In this study, we developed environment-responsive drug delivery system (FM@IQ/PST&ZIF-8/DOX) based on ZIF-8 for tumor photothermal/immunotherapy/chemotherapy synergistic therapy. The prepared FM@IQ/PST&ZIF-8/DOX nanoplatfrom not only has highly drug loading capacity for chemotherapeutic drug-doxorubicin, but also erythrocyte membrance modified on their surface can endow their immunity-escaping property and prolong their blood circulation time. More important, the neurotransmitter serotonin was encapsulated on the surface of ZIF-8/DOX by oxidative polymerization, which can effectively avoid the premature leakage of DOX in the blood circulation. And the formed polyserotonin shell has superior photothermal conversion performance, as well as the adsorption property of polyserotonin shell was utilized to load imiqumod. When FM@IQ/PST&ZIF-8/DOX entered the tumor tissue, the surface modified folate molecules can specifically bind to the folate receptors on the surface of tumor cells to improve FM@IQ/PST&ZIF-8/DOX uptake by tumor cells. In vitro and in vivo results showed that FM@IQ/PST&ZIF-8/DOX nanoplatform could generate a large amount of heat under near-infrared light irradiation, and then induce the apoptosis of tumor cells, release tumor associated antigens, and effectively solve the problem of tumor heterogeneity. In addition, the loaded imiquimod could effectively improve the immunosuppressive microenvironment, enhance the body's anti-tumor immune response, to inhibit tumor metastasis and recurrence. Therefore, the novel FM@IQ/PST&ZIF-8/DOX nanoplatform designed in this research can not only achieve controllable and precise drug release, but also it is expected to become a promising new strategy for tumor treatment and provide corresponding inspiration for the later research and development of environment-responsive drugs. [ABSTRACT FROM AUTHOR]

Despite the tremendous potential of DNAzymes in gene therapy, achieving gene regulation with spatiotemporal precision and satisfactory efficacy remains a key challenge. Herein, we developed a near‐infrared light (NIR)‐triggered cascade effect system that enables precise spatiotemporal gene silencing and gas‐synergistic cancer therapy. This nanoplatform was constructed using an enzyme‐activatable DNAzyme, a nitric oxide (NO) precursor, and upconversion nanoparticles (UCNPs). The UCNPs act as light converters, facilitating the precursor to produce NO under NIR light irradiation, while the generated NO not only participates directly in gas therapy but also induces the upregulation of cytoplasmic APE1 level, resulting in enhanced DNAzyme activation and spatially controlled gene silencing. By leveraging this mechanism, cascade effects mediated gas‐gene synergistic therapy is achieved through the combination of NIR light‐controlled NO release and APE1‐activatable gene therapy. We demonstrated that this nanoplatform enables enhanced anti‐tumor effects both in vitro and in vivo. This strategy represents a critical step forward in the quest for highly targeted and efficient cancer treatments. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is characterized by dopamine (DA) neuron loss and neuroinflammation. This study develops carrier‐free nanocapsules (NCs) for targeted delivery of DA and catalase (CAT) to the PD brain, addressing both DA depletion and neuroinflammation simultaneously. The NCs are engineered by DA and 4‐formylphenylboronic acid co‐loading with cRGD‐modified CAT (CAT‐cRGD) and surface‐modifying with Angiopep‐2 (Ang). Ang targets the blood‐brain barrier (BBB), enhancing brain delivery, while cRGD targets upregulated integrin receptors in the PD‐affected BBB. The NCs showed a 1.4‐fold increase in parkinsonian brain targeting efficiency compared to normal mice. In PD mice models, NCs demonstrated a stable increase in learning and memory, enhanced locomotor activity, and improved motor coordination. DA supplementation significantly enhanced dopaminergic signaling, increasing DA levels 1.8‐ and 3.5‐fold in the striatum and substantia nigra, respectively. Additionally, delivered CAT effectively reduced neuroinflammation by mitigating endoplasmic reticulum stress, slowing disease progression, and protecting DA from oxidation. This innovative approach using PD‐targeted NCs represents a synergistic strategy for PD treatment, combining symptomatic relief with disease progression intervention. [ABSTRACT FROM AUTHOR]

Nanoformulations with endogenous/exogenous stimulus‐responsive characteristics show great potential in tumor cell elimination with minimal adverse effects and high precision. Herein, an intelligent nanotheranostic platform (denoted as TPZ@Cu‐SnS2‐x/PLL) for tumor microenvironment (TME) and near‐infrared light (NIR) activated tumor‐specific therapy is constructed. Copper (Cu) doping and the resulting sulfur vacancies can not only improve the response range of visible light but also improve the separation efficiency of photogenerated carriers and increase the carrier density, resulting in the ideal photothermal and photodynamic performance. Density functional theory calculations revealed that the introduction of Cu and resulting sulfur vacancies can induce electron redistribution, achieving favorable photogenerated electrons. After entering cells through endocytosis, the TPZ@Cu‐SnS2‐x/PLL nanocomposites show the pH responsivity property for the release of the TPZ selectively within the acidic TME, and the released Cu2+ can first interact with local glutathione (GSH) to deplete GSH with the production of Cu+. Subsequently, the Cu+‐mediated Fenton‐like reaction can decompose local hydrogen peroxide into hydroxyl radicals, which can also be promoted by hyperthermia derived from the photothermal effect for tumor cell apoptosis. The integration of photoacoustic/computed tomography imaging‐guided NIR phototherapy, TPZ‐induced chemotherapy, and GSH‐elimination/hyperthermia enhanced chemodynamic therapy results in synergistic therapeutic outcomes without obvious systemic toxicity in vivo. [ABSTRACT FROM AUTHOR]

Bacterial infection is a major impediment towards wound healing and threaten human health worldwide. Traditional antibiotic therapy poses a high risk of inducing bacterial resistance, thus nanomaterial-based synergistic bactericidal strategy as effective alternatives have received tremendous attention. Herein, a NIR/pH-dual responsive nanoplatform was fabricated for synergistic photothermal and chemodynamic therapy (PTT/CDT). Prussian blue (PB) were employed as supporting material, while copper peroxide (CP) were growth in situ on PB surface, resulting in a core-shell structured nanoplatform (designated as PC). PB core served as photothermal/Fenton catalyst dual agents, and CP shell could co-release Cu2+ and H 2 O 2 under acidic bacterial infection environment, realizing synergistic PTT and H 2 O 2 -releasing CDT. Under NIR irradiation, PC exhibited photothermal-enhanced Fenton-like reaction feature and the hyperthermia facilitated Cu2+ release, leading to the rapid conversion of H 2 O 2 into toxic •OH to effectively kill Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. aureus), eradicating S. aureus biofilm. Moreover, the released Cu2+ could improve the bactericidal effect of CDT via the depletion of GSH and significantly promote cell migration. Furthermore, in vivo experiments demonstrated PC with good biocompatibility exhibited robust bactericidal effect and promoted wound healing. Overall, this versatile nanoplatform offered an efficacious and safe antibiotic-free strategy for bacterial infection treatments. Core-shell structured PC are designed for effective bacterial elimination via photothermal-enhanced and H 2 O 2 -releasing chemodynamic therapy. [Display omitted] • The versatile nanoplatform (PB@CP) was prepared via a facile in situ growth method. • NIR-responsive PB@CP released Cu2+ and H 2 O 2 at acidic pH to achieve enhanced CDT. • PB@CP exhibited synergistic antibacterial effect of mild-temperature PTT and CDT. • PB@CP showed astonishing broad-spectrum antibacterial and anti-biofilm properties. • PB@CP exhibited excellent healing performance on bacterial-infected wound. [ABSTRACT FROM AUTHOR]

The advancement of rational nano drug delivery systems offers robust tools for achieving synergistic therapeutic outcomes in tumor treatment. In this study, we present the development of pH and near-infrared laser dual-responsive nanoparticles (DOX-CuS@CaCO 3 @PL-PEG, DCCP NPs) based on calcium carbonate, utilizing a one-pot gas diffusion reaction. These nanoparticles enable combined photothermal therapy (PTT), chemodynamic therapy (CDT), chemotherapy, and Ca2+-overloading synergistic therapy. Doxorubicin (DOX) and copper sulfide (CuS) NPs were co-loaded in CaCO 3 , followed by PEG surface functionalization. The presence of PEG enhanced the stability of DCCP NPs in aqueous environments. Controlled release of DOX, CuS NPs, and Ca2+ occurs specifically in the acidic tumor microenvironment. Released DOX enhances chemotherapy efficiency, while CuS NPs, upon laser irradiation, induce thermal damage, promoting further drug release and cellular uptake. Additionally, CuS NPs in our system consume excess GSH and generate toxic hydroxyl radicals (·OH) through a Fenton-like reaction, contributing to CDT. These radicals not only directly eliminate tumor cells but also disrupt mitochondrial Ca2+ buffering capacity. Furthermore, Ca2+ released from CaCO 3 induces Ca2+-overloading, intensifying mitochondrial disruption and oxidative damage. The synergistic combination of PTT, CDT, chemotherapy, and Ca2+-overloading showcases significant therapeutic potential, indicating broad applications in tumor therapy. This multifaceted approach holds promise for advancing the field of tumor therapeutics. pH and NIR laser dual-responsive multimodal nanoplatform DCCP NPs can achieve Ca2+-overloading therapy, PTT, CDT and chemotherapy after entering tumor tissues and irradiated by NIR laser. Photothermal light improves chemotherapy effect and CDT efficiency, while ROS generated by CDT disrupts Ca2+ buffer capacity and synergizes with CaCO 3 degradation to release large amount of Ca2+, leading to Ca2+-overloading. [Display omitted] • CuS NPs produce effective thermal ablation under NIR laser irradiation. • Photothermal promotes CuS-mediated Fenton-like catalytic activityto generate ROS. • The large amount of Ca2+ released by CaCO 3 degradation causes Ca2+-overloading to damage mitochondria. • Dual-responsive multimodal nanoplatform achieves enhanced cancer therapeutic effects. [ABSTRACT FROM AUTHOR]

The development of synergistic therapy that integrates various therapeutic approaches has become an emerging antitumor treatment strategy. In this study, we developed a polydopamine-modified nanodelivery system loaded with honokiol (HNK), leveraging the high porosity and large specific surface area of ZIF-90. This system combines the chemotherapeutic effects of HNK, a bioactive compound derived from traditional Chinese medicine, with photothermal therapy (PTT) mediated by polydopamine. The resulting P-Z-HNK nanoparticles, with an average size of 100.03 ± 20.06 nm and a high drug loading capacity of 50.04 ± 0.58%, demonstrated excellent photothermal effects and stability following near-infrared (NIR) laser irradiation, leading to efficient melanoma cell ablation. Moreover, the combination of PTT and enhanced chemotherapy not only effectively inhibited melanoma cell proliferation but also significantly reduced cell migration and metastasis. Both in vitro and in vivo experiments demonstrated that the dual-modality treatment with P-Z-HNK under NIR laser irradiation achieved superior antimelanoma efficacy compared to monotherapy. Furthermore, biosafety assessments revealed no significant acute toxicity associated with P-Z-HNK. These results indicate that P-Z-HNK offers a promising nanoplatform for synergistic melanoma therapy, providing a potent approach to overcoming the limitations of single-modal treatments. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM), a highly invasive type of brain tumor located within the central nervous system, manifests a median survival time of merely 14.6 months. Radiotherapy kills tumor cells through focused high-energy radiation and has become a crucial treatment strategy for GBM, especially in cases where surgical resection is not viable. However, the presence of radioresistant tumor cells limits its clinical effectiveness. Radioresistance is a key factor of treatment failure, prompting the development of various therapeutic strategies to overcome this challenge. With the rapid development of nanomedicine, nanoradiosensitizers provide a novel approach to enhancing the effectiveness of radiotherapy. In this review, we discuss the reasons behind GBM radio-resistance and the mechanisms of radiotherapy sensitization. Then we summarize the primary types of nanoradiosensitizers and recent progress in their application for the radiosensitization of GBM. Finally, we elucidate the factors influencing their practical implementation, along with the challenges and promising prospects associated with multifunctional nanoradiosensitizers. Article highlights Enhanced radiosensitivity Nanoradiosensitizers significantly improve the radiosensitivity of glioblastoma, leading to more effective radiotherapy outcomes and reduced tumor resistance. Targeted delivery Nanoradiosensitizers can be engineered to selectively target glioma cells, minimizing damage to surrounding healthy brain tissue and enhancing the therapeutic index. Synergistic therapies Nanoradiosensitizers can be integrated with other treatments, such as chemotherapy or immunotherapy, to create synergistic effects that further inhibit glioma progression and improve patient outcomes. [ABSTRACT FROM AUTHOR]

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Abstract Cancer therapy continues to face critical challenges, including drug resistance, recurrence, and severe side effects, which often compromise patient outcomes and quality of life. Exploring novel, cost-effective approaches, this review highlights the potential of Piper nigrum (black pepper) extract (PNE) as a complementary anticancer agent. Piper nigrum, a widely available spice with a rich history in traditional medicine, contains bioactive compounds such as piperine, which have demonstrated significant anticancer activities including cell cycle arrest, apoptosis induction, and inhibition of tumor growth and metastasis. The review evaluates the recent findings from in vitro, in vivo, and clinical studies, emphasizing PNE's capacity to enhance the efficacy of conventional chemotherapeutic agents while mitigating their side effects. Key mechanisms underlying these effects include oxidative stress modulation, suppression of pro-metastatic factors, and synergistic interactions with established drugs like doxorubicin and paclitaxel. These interactions suggest that PNE could play a pivotal role in overcoming chemoresistance and improving therapeutic outcomes. Furthermore, this review highlights the potential benefits of PNE in resource-limited settings, where the cost of cancer treatments often restricts access. However, challenges such as compositional variability, limited bioavailability, and the need for standardization and clinical validation need to be addressed to advance the integration of PNE into basic oncology. By providing a comprehensive analysis of the anticancer mechanisms of PNE and its potential as a cost-effective adjuvant therapy, this review provides new insight into the exploitation of Piper nigrum to improve cancer treatment efficacy while reducing side effects. Future research directions are discussed to address current limitations and facilitate clinical translation.

Non-small cell lung cancer (NSCLC) is a major disease with high incidence, low survival rate and prone to develop drug resistance to chemotherapy. The mechanism of secondary drug resistance in NSCLC chemotherapy is very complex, and studies have shown that the abnormal activation of STAT3 (Signal Transducer and Activator of Transcription 3) plays an important role in it. In this study, the pGPU6/GFP/Neo STAT3-shRNA recombinant plasmid was constructed with STAT3 as the precise target. By modifying hydrophilic and hydrophobic blocks onto chitosan, a multifunctional vitamin E succinate-chitosan-polyethylene glycol monomethyl ether histidine (VES-CTS-mPEG-His) micelles were synthesized. The micelles could encapsulate hydrophobic drug doxorubicin through self-assembly, and load the recombinant pGPU6/GFP/Neo STAT3-shRNA (pDNA) through positive and negative charges to form dual-loaded nanoparticles DOX/VCPH/pDNA. The co-delivery and synergistic effect of DOX and pDNA could up-regulate the expression of PTEN (Phosphatase and Tensin Homolog), down-regulate the expression of CD31, and induce apoptosis of tumor cells. The results of precision targeted therapy showed that DOX/VCPH/pDNA could significantly down-regulate the expression level of STAT3 protein, further enhancing the efficacy of chemotherapy. Through this study, precision personalized treatment of NSCLC could be effectively achieved, reversing its resistance to chemotherapy drugs, and providing new strategies for the treatment of drug-resistant NSCLC.

Yong-Gyu Jeong,1 Joo-Hwan Park,2 Dongwoo Khang1,3,4 1Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, South Korea; 2Division of Medical Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, College of Medicine, Gachon University, Incheon, 21565, South Korea; 3Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 21999, South Korea; 4Department of Physiology, College of Medicine, Gachon University, Incheon, 21999, South KoreaCorrespondence: Dongwoo Khang, Department of Physiology, College of Medicine, Gachon University, Incheon, 21999, South Korea, Tel +82 32 899 1525, Email dkhang@gachon.ac.kr Joo-Hwan Park, Division of Medical Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University, Incheon, 21565, South Korea, Tel +82-32-460-3229, Email replica1874@gilhospital.comAbstract: The advent of acoustically responsive nanodrugs that are specifically optimized for sonodynamic therapy (SDT) is a novel approach for clinical applications. Examining the therapeutic applications of sono-responsive drug delivery systems, understanding their dynamic response to acoustic stimuli, and their crucial role in enhancing targeted drug delivery are intriguing issues for current cancer treatment. Specifically, the suggested review covers SDT, a modality that enhances the cytotoxic activity of specific compounds (sonosensitizers) using ultrasound (US). Notably, SDT offers significant advantages in cancer treatment by utilizing US energy to precisely target and activate sonosensitizers toward deep-seated malignant sites. The potential mechanisms underlying SDT involve the generation of radicals from sonosensitizers, physical disruption of cell membranes, and enhanced drug transport into cells via US-assisted sonoporation. In particular, SDT is emerging as a promising modality for noninvasive, site-directed elimination of solid tumors. Given the complexity and diversity of tumors, many studies have explored the integration of SDT with other treatments to enhance the overall efficacy. This trend has paved the way for SDT-based multimodal synergistic cancer therapies, including sonophototherapy, sonoimmunotherapy, and sonochemotherapy. Representative studies of these multimodal approaches are comprehensively presented, with a detailed discussion of their underlying mechanisms. Additionally, the application of audible sound waves in biological systems is explored, highlighting their potential to influence cellular processes and enhance therapeutic outcomes. Audible sound waves can modulate enzyme activities and affect cell behavior, providing novel avenues for the use of sound-based techniques in medical applications. This review highlights the current challenges and prospects in the development of SDT-based nanomedicines in this rapidly evolving research field. The anticipated growth of this SDT-based therapeutic approach promises to significantly improve the precision of cancer treatment. Keywords: sonodynamic therapy, ultrasound, synergistic therapy, sonosensitizer, nanomedicine, cancer treatment, acoustic audible wave

Multivalent DNA probes were creatively designed and decorated on small extracellular vesicles for precise tumor targeting and enhanced synergistic therapy. [Display omitted] • The engineered sEVs achieved precise tumor targeting and synergistic therapy. • Multivalent DNA probes were designed to enhance targeting ability. • Telomerase triggered intracellular nanocarriers aggregation was creatively proposed. • The nanocarrier enables site-specific and photo-controlled drug release. Small extracellular vesicles (sEVs) have gained wide attention as efficient carriers for disease treatment. However, the proclivity of sEVs to be ingested by source cells is insufficient to accurately target specific sites, posing a challenge in realizing controlled targeting treatment. Here, we developed an engineered sEV nanocarrier capable of precise tumor targeting and enhanced synergistic therapy. Multivalent DNA probes, comprising abundant AS1411 aptamers and telomerase primers, were innovatively modified on the sEV membrane (M-D-sEV) for precise tumor targeting. To achieve synergistic therapy, gold nanorod-cerium oxide nanostructures (Au NRs-CeO 2) and manganese dioxide nanosheets-doxorubicin (MnO 2 NSs-DOX) were encapsulated into liposomes (Lip-Mat). Then M-D-sEV and Lip-Mat were fused together through membrane fusion to obtain nanocarriers. Owing to the multivalence of the probes, the surface of the nanocarriers was loaded with numerous aptamers, which greatly enhances their targeting ability and promotes the accumulation of drugs. When nanocarriers were ingested by tumor cells, telomerase and multivalent DNA probes triggered their aggregation, enhancing the therapeutic effect. Furthermore, under laser irradiation, Au NRs-CeO 2 converted light into hyperthermia, thereby inducing the destruction of nanocarriers membrane. This process initiated a series of reactions involving glutathione and H 2 O 2 consumption, as well as DOX release, ultimately achieving synergistic tumor therapy. In vitro and in vivo studies demonstrated the remarkable targeting ability of multivalent DNA probes and excellent therapeutic effect of this strategy. The engineered strategy of sEVs provide a promising approach for precise tumor therapy and hold great potential for the development of efficient, safe, and personalized drug delivery systems. [ABSTRACT FROM AUTHOR]

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.

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

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

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]

Photo‐triggered ROS‐responsive supramolecular nanoprodrugs (BNN6@GBTC NPs) are constructed via supramolecular self‐assembly of amphiphilic prodrug molecule (GBTC) and NO donor (BNN6). BNN6@GBTC NPs possess good stability, ROS responsiveness, and selective HepG2 cells targetability via overexpressed galactose receptors on the cell membrane. When BNN6@GBTC NPs are taken up by HepG2 cells, they can generate ROS upon light irradiation, which can not only be used for photodynamic therapy, but also cleave the thioketal linkage to release camptothecin for chemotherapy. Meanwhile, BNN6 triggering release NO for gas therapy. BNN6@GBTC NPs enable targeted and synergistic chemo/photodynamic/gas therapy, which results in reduced damage to normal cells and enhanced anti‐cancer efficacy in vitro. This work provides a novel approach for the design of nanoprodrugs based on supramolecular self‐assembly to achieve the multimodal synergistic anti‐cancer therapy. [ABSTRACT FROM AUTHOR]

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]

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]

Theranostics, integrating diagnostic and therapeutic functionalities, have emerged as advanced systems for timely cancer diagnosis and effective treatment. The development of versatile materials suitable for cancer theranostics is intensifying. Porphyrin-based metal-organic frameworks (MOFs) leverage the structural diversity and designability inherent in MOFs, alongside the robust photophysical, catalytic, and biological properties of porphyrins. These materials enhance the solubility and stability of porphyrins and facilitate their stable functionalized assemblies, conferring the potential for multimodal imaging diagnostics and precision therapeutics. In this review, we summarized the potential of porphyrin-based MOFs as cancer theranostics platforms, focusing on recent advancements in porphyrin-based MOFs, and highlighting their functionalized strategies and developments in diagnostic imaging and synergistic therapies. Finally, we proposed the challenges and prospects of these emerging materials in cancer theranostics.

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.