Impact of dietary ingredients on radioprotection and radiosensitization: a comprehensive review.

Radiation exposure poses significant health risks, particularly in radiotherapy and nuclear accidents. Certain dietary ingredients offer potential radioprotection and radiosensitization. In this review, we explore the impact of dietary ingredients, including vitamins, minerals, antioxidants, and other bioactive compounds, on radiation sensitivity and their potential for radioprotection. Radiosensitizers reoxygenate hypoxic tumor cells, increase the radiolysis of water molecules, and regulate various molecular mechanisms to induce cytotoxicity and inhibit DNA repair in irradiated tumor cells. Several dietary ingredients, such as vitamins C, E, selenium, and phytochemicals, show promise in protecting against radiation by reducing radiation-induced oxidative stress, inflammation, and DNA damage. Radioprotectors, such as ascorbic acid, curcumin, resveratrol, and genistein, activate and modulate various signaling pathways, including Keap1-Nrf2, NF-κB, PI3K/Akt/mammalian target of rapamycin (mTOR), STAT3, and mitogen-activated protein kinase (MAPK), in response to radiation-induced oxidative stress, regulating inflammatory cytokine expression, and promoting DNA damage repair and cell survival. Conversely, natural dietary radiosensitizers impede these pathways by enhancing DNA damage and inducing apoptosis in irradiated tumor cells. Understanding the molecular basis of these effects may aid in the development of effective strategies for radioprotection and radiosensitization in cancer treatment. Dietary interventions have the potential to enhance the efficacy of radiation therapy and minimize the side effects associated with radiation exposure.

Lipiodol emulsion as a dual chemoradiation-sensitizer for pancreatic cancer treatment.

Pancreatic ductal adenocarcinoma (PDAC) has a low survival rate and limited treatment options. Concurrent chemoradiotherapy is considered beneficial to improve tumor control, but the low drug bioavailability at tumor site and the low radiation tolerance of surrounding healthy organs greatly limits its effectiveness. Lipiodol, a natural drug carrier used in clinical transarterial chemoembolization, has shown potential as a radiosensitizer due to its high Z element iodine composition. Thus, this study aims to repurpose lipiodol as a sensitizer to simultaneously enhance chemo- and radiotherapy for PDAC. To this end, a stable lipiodol emulsion (IOE) loaded with gemcitabine is designed using clinically approved surfactants. At in vivo level, IOE demonstrates better radiotherapeutic effect than existing nanoradiosensitizers and enhanced drug bioavailability over free drug, leading to significant tumor inhibition and improved survival rates under concurrent chemo-radiotherapy. This may due to the sustained drug release, homogenous spatial distribution, and long-term retention ability of IOE in solid PDAC tumor. Furthermore, to better understand the functioning mechanism of drug-loaded IOE, in vitro study is conducted to reveal the ROS- and DNA damage-related therapeutic pathways. Lastly, a comprehensive toxicity assessment also proves the good biocompatibility and safety of as-prepared IOE. This study offers a clinically feasible sensitizer for simultaneous chemoradiotherapy and holds potential for other types of cancer treatment in clinics.

Chemoradiotherapy and nanomedicine: Drug mechanisms and delivery systems.

Radiotherapy is an invaluable tool in the treatment of cancer. However, when used as a monotherapy, it fails to provide curative outcomes. Chemotherapy drugs are often included to boost the effects of radiation. Key classes of radiosensitizing drugs include platinum compounds, anthracyclines, antimetabolites, taxanes, topoisomerase inhibitors, alkylating agents, and DNA damage repair inhibitors. Chemoradiotherapy suffers from not only systemic toxicities from chemotherapy drugs but also synergistic radiation toxicity as well. It is critical to deliver radiosensitizing molecules to tumor cells while avoiding adjacent healthy tissues. Currently, nanomedicine provides an avenue for tumor specific delivery of radiosensitizers. Nanoscale delivery vehicles can be synthesized from lipids, polymers, or inorganic materials. Additionally, nanomedicine encompasses stimuli responsive particles including prodrug formulation for tumor specific activation. Clinically, nanomedicine and radiotherapy are intertwined with approved formulation including DOXIL and Abraxane. Though many challenges remain, the ongoing progress evidences a promising future for both nanomedicine and chemoradiotherapy. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Baicalein Enhances Radiosensitivity in Colorectal Cancer via JAK2/STAT3 Pathway Inhibition.

Radiation resistance is a crucial factor influencing therapeutic outcomes in colorectal cancer (CRC). Baicalein (BE), primarily derived from Scutellaria baicalensis, has demonstrated anti-CRC properties. However, the impact of BE on the radiosensitivity of CRC remains unclear. This study aimed to evaluate the radiosensitization effects of BE and elucidate its mechanism in CRC radiotherapy. We established an in vitro radioresistant cell model (CT26-R) using parental CRC cells (CT26) subjected to ionizing radiation (IR). CT26-R cells were pretreated with or without BE, followed by transfection with pcDNA-NC and pcDNA-JAK2. The proliferation of CT26-R cells treated with BE and IR was assessed using a colony formation assay. A CRC animal model was developed in BALB/c mice via CT26-R cell transplantation. The radiosensitizing effect of BE on CRC was evaluated in vivo. TUNEL assay was conducted to detect apoptosis in tumor tissue. The expression levels of p-STAT3, JAK2, PD-L1, and SOCS3 in vitro and in vivo were measured by western blotting. Our results demonstrated that BE significantly increased radiosensitivity in vitro and in vivo and enhanced apoptosis in tumor tissues. Additionally, BE significantly downregulated the expression of p-STAT3, JAK2, and PD-L1, and significantly upregulated SOCS3 expression. These in vivo effects were reversed by pcDNA-JAK2. In summary, our data suggest that BE enhances CRC radiosensitivity by inhibiting the JAK2/STAT3 pathway.

Arsenic sulfide enhances radiosensitivity in rhabdomyosarcoma via activating NFATc3-RAG1 mediated DNA double strand break (DSB).

Rhabdomyosarcoma (RMS) represents one of the most lethal soft-tissue sarcomas in children. The toxic trace element arsenic has been reported to function as a radiosensitizer in sarcomas. To investigate the role of arsenic sulfide (As4S4) in enhancing radiation sensitization in RMS, this study was conducted to elucidate its underlying mechanism in radiotherapy. The combination of As4S4 and radiotherapy showed significant inhibition in RMS cells, as demonstrated by the cell counting kit-8 (CCK-8) assay and flow cytometry. Subsequently, we demonstrated for the first time that As4S4, as well as the knockdown of NFATc3 led to double-strand break (DSB) through increased expression of RAG1. In vivo experiment confirmed that co-treatment efficiently inhibited RMS growth. Furthermore, survival analysis of a clinical cohort consisting of 59 patients revealed a correlation between NFATc3 and RAG1 expression and overall survival (OS). Cox regression analysis also confirmed the independent prognostic significance of NFATc3 and RAG1.Taken together, As4S4 enhances radiosensitivity in RMS via activating NFATc3-RAG1 mediated DSB. NFATc3 and RAG1 are potential therapeutic targets. As4S4 will hopefully serve as a prospective radio-sensitizing agent for RMS.

"Abraxane-Like" Radiosensitizer for In Situ Oral Cancer Therapy.

Radiotherapy plays a vital role in cancer therapy. However, the hypoxic microenvironment of tumors greatly limits the effectiveness, thus it is crucial to develop a simple, efficient, and safe radiosensitizer to reverse hypoxia and ameliorate the efficacy of radiotherapy. Inspired by the structure of canonical nanodrug Abraxane, herein, a native HSA-modified CaO2 nanoparticle system (CaO2-HSA) prepared by biomineralization-induced self-assembly is developed. CaO2-HSA will accumulate in tumor tissue and decompose to produce oxygen, altering the hypoxic condition inside the tumor. Simultaneously, ROS and calcium ions will lead to calcium overload and further trigger immunogenic cell death. Notably, its sensitizing enhancement ratio (SER = 3.47) is much higher than that of sodium glycididazole used in the clinic. Furthermore, in animal models of in situ oral cancer, CaO2-HSA can effectively inhibit tumor growth. With its high efficacy, facile preparation, and heavy-metal free biosafety, the CaO2-HSA-based radiosensitizer holds enormous potential for oral cancer therapy.

Concurrent chemoradiation with low-dose and long-duration weekly infusion of gemcitabine in unresectable squamous cell carcinoma of head and neck (SCCHN).

BACKGROUND: Concurrent chemoradiotherapy now represents the standard of care in locally advanced unresectable squamous cell carcinoma of the head and neck, and the administration of cisplatin in triweekly or weekly schedules is the most commonly used chemotherapeutic agent. However, the chemotherapeutic agent and its scheduling with radiation is still an area of investigation with safer toxicity profile and better response rates. Gemcitabine is a potent radiosensitizer, and non-cytotoxic concentration results in decreased systemic toxicity while maintaining radiosensitization properties. Furthermore, data are emerging for low-dose and long-duration infusion where this strategy is found to be effective and a safe alternative to standard brief infusion. Based on these two strategies, that is, non-cytotoxic concentration with long duration, we have explored the unique possibility of further lowering the toxicity profile without compromising the efficacy. METHOD: Eligible patients of locally advanced unresectable squamous cell carcinoma of the head and neck underwent radiation treatment with concurrent gemcitabine. A total dose of 70 Gy in 35 fractions over a period of seven weeks with conventional fractionation schedule was delivered with cord off after 44 Gy. Concurrent gemcitabine was administered intravenously for over two hours once a week, 1-2 h before radiation and for seven consecutive weeks at 50 mg/m2. RESULT: Fifty-two patients was enrolled in this study, out of which 41 completed the treatment. Fifty-nine percent completed treatment within seven weeks. Sixty-four percent were found to have received more than five cycles. Mean follow-up of patients was found to be 4.9 months. Sixty-eight percent had complete response. Stage III patients achieved more complete response compared to stage IV. There was no site-wise difference in achieving complete response. Patients who have received less than five chemo cycles or completed the treatment in more than seven weeks had less complete response. Sixty-one percent had severe mucositis while 39% developed mild/moderate mucositis. Considering skin toxicity, 80% were found to have mild/moderate skin toxicity, while only 20% suffered from severe grades of skin toxicity. CONCLUSION: Gemcitabine in low-dose and long-duration infusion is a potent radiosensitizer with safer hematological toxicity and manageable local toxicities.

Progression in low-intensity ultrasound-induced tumor radiosensitization.

BACKGROUND: Radiotherapy (RT) is a widely utilized tumor treatment approach, while a significant obstacle in this treatment modality is the radioresistance exhibited by tumor cells. To enhance the effectiveness of RT, scientists have explored radiosensitization approaches, including the use of radiosensitizers and physical stimuli. Nevertheless, several approaches have exhibited disappointing results including adverse effects and limited efficacy. A safer and more effective method of radiosensitization involves low-intensity ultrasound (LIUS), which selectively targets tumor tissue and enhances the efficacy of radiation therapy. METHODS: This review summarized the tumor radioresistance reasons and explored LIUS potential radiosensitization mechanisms. Moreover, it covered diverse LIUS application strategies in radiosensitization, including the use of LIUS alone, ultrasound-targeted intravascular microbubble destruction, ultrasound-mediated targeted radiosensitizers delivery, and sonodynamic therapy. Lastly, the review presented the limitations and prospects of employing LIUS-RT combined therapy in clinical settings, emphasizing the need to connect research findings with practical applications. RESULTS AND CONCLUSION: LIUS employs cost-effective equipment to foster tumor radiosensitization, curtail radiation exposure, and elevate the quality of life for patients. This efficacy is attributed to LIUS's ability to utilize thermal, cavitation, and mechanical effects to overcome tumor cell resistance to RT. Multiple experimental analyses have underscored the effectiveness of LIUS in inducing tumor radiosensitization using diverse strategies. While initial studies have shown promising results, conducting more comprehensive clinical trials is crucial to confirm its safety and effectiveness in real-world situations.

Targeting mTOR and survivin concurrently potentiates radiation therapy in renal cell carcinoma by suppressing DNA damage repair and amplifying mitotic catastrophe.

BACKGROUND: Renal cell carcinoma (RCC) was historically considered to be less responsive to radiation therapy (RT) compared to other cancer indications. However, advancements in precision high-dose radiation delivery through single-fraction and multi-fraction stereotactic ablative radiotherapy (SABR) have led to better outcomes and reduced treatment-related toxicities, sparking renewed interest in using RT to treat RCC. Moreover, numerous studies have revealed that certain therapeutic agents including chemotherapies can increase the sensitivity of tumors to RT, leading to a growing interest in combining these treatments. Here, we developed a rational combination of two radiosensitizers in a tumor-targeted liposomal formulation for augmenting RT in RCC. The objective of this study is to assess the efficacy of a tumor-targeted liposomal formulation combining the mTOR inhibitor everolimus (E) with the survivin inhibitor YM155 (Y) in enhancing the sensitivity of RCC tumors to radiation. EXPERIMENTAL DESIGN: We slightly modified our previously published tumor-targeted liposomal formulation to develop a rational combination of E and Y in a single liposomal formulation (EY-L) and assessed its efficacy in RCC cell lines in vitro and in RCC tumors in vivo. We further investigated how well EY-L sensitizes RCC cell lines and tumors toward radiation and explored the underlying mechanism of radiosensitization. RESULTS: EY-L outperformed the corresponding single drug-loaded formulations E-L and Y-L in terms of containing primary tumor growth and improving survival in an immunocompetent syngeneic mouse model of RCC. EY-L also exhibited significantly higher sensitization of RCC cells towards radiation in vitro than E-L and Y-L. Additionally, EY-L sensitized RCC tumors towards radiation therapy in xenograft and murine RCC models. EY-L mediated induction of mitotic catastrophe via downregulation of multiple cell cycle checkpoints and DNA damage repair pathways could be responsible for the augmentation of radiation therapy. CONCLUSION: Taken together, our study demonstrated the efficacy of a strategic combination therapy in sensitizing RCC to radiation therapy via inhibition of DNA damage repair and a substantial increase in mitotic catastrophe. This combination therapy may find its use in the augmentation of radiation therapy during the treatment of RCC patients.

Application of High-Z Nanoparticles to Enhance Current Radiotherapy Treatment.

Radiotherapy is an essential component of the treatment regimens for many cancer patients. Despite recent technological advancements to improve dose delivery techniques, the dose escalation required to enhance tumor control is limited due to the inevitable toxicity to the surrounding healthy tissue. Therefore, the local enhancement of dosing in tumor sites can provide the necessary means to improve the treatment modality. In recent years, the emergence of nanotechnology has facilitated a unique opportunity to increase the efficacy of radiotherapy treatment. The application of high-atomic-number (Z) nanoparticles (NPs) can augment the effects of radiotherapy by increasing the sensitivity of cells to radiation. High-Z NPs can inherently act as radiosensitizers as well as serve as targeted delivery vehicles for radiosensitizing agents. In this work, the therapeutic benefits of high-Z NPs as radiosensitizers, such as their tumor-targeting capabilities and their mechanisms of sensitization, are discussed. Preclinical data supporting their application in radiotherapy treatment as well as the status of their clinical translation will be presented.

Radiosensitization effect of quinoline-indole-schiff base derivative 10E on non-small cell lung cancer cells in vitro and in tumor xenografts.

Radioresistance is an inevitable obstacle in the clinical treatment of inoperable patients with non-small cell lung cancer (NSCLC). Combining treatment with radiosensitizers may improve the efficacy of radiotherapy. Previously, the quinoline derivative 10E as new exporter of Nur77 has shown superior antitumor activity in hepatocellular carcinoma. Here, we aimed to investigate the radiosensitizing activity and acting mechanisms of 10E. In vitro, A549 and H460 cells were treated with control, ionizing radiation (IR), 10E, and 10E + IR. Cell viability, apoptosis, and cycle were examined using CCK-8 and flow cytometry assays. Protein expression and localization were examined using western blotting and immunofluorescence. Tumor xenograft models were established to evaluate the radiosensitizing effect of 10E in vivo. 10E significantly inhibited cell proliferation and increased their radiosensitivity while reducing level of p-BCRA1, p-DNA-PKs, and 53BP1 involved in the DNA damage repair pathway, indicating that its radiosensitizing activity is closely associated with repressing DNA damage repair. A549 cells showed low level of Nur77 and a low response to IR but 10E-treated A549 cells showed high level of Nur77 indicating that Nur77 is a core radiosensitivity factor and 10E restores the expression of Nur77. Nur77 and Ku80 extranuclear co-localization in the 10E-treated A549 cells suggested that 10E-modulated Nur77 nuclear exportation inhibits DNA damage repair pathways and increases IR-triggered apoptosis. The combination of 10E and IR significantly inhibits tumor growth in a tumor xenograft model. Our findings suggest that 10E acts as a radiosensitizer and that combining 10E with radiotherapy may be a potential strategy for NSCLC treatment.

Bismuth Nanoparticles Increase Effectiveness of Proton Therapy of Ehrlich Carcinoma.

We studied the antitumor activity of the combined use of local proton irradiation in two modes (10 and 31 Gy) with preliminary intra-tumoral injection of two types of bismuth nanoparticles differing in surface coating: coated with the amphiphilic molecule Pluronic-F127 or Silane-PEG (5 kDa)-COOH polymer. Nanoparticles were used in doses of 0.75 and 1.5 mg/mouse. In two independent series on experimental tumor model (solid Ehrlich carcinoma), bismuth nanoparticles of both modifications injected directly into the tumor enhanced the antitumor effects of proton therapy. Moreover, the radiosensitizing effect of bismuth nanoparticles administered via this route increased with the increasing the doses of nanoparticles and the doses of radiation exposure. In our opinion, these promising data obtained for the first time extend the possibilities of treating malignant neoplasms.

Janus ACSP Nanoparticle for Synergistic Chemodynamic Therapy and Radiosensitization.

Protective autophagy and DNA damage repair lead to tumor radio-resistance. Some hypoxic tumors exhibit a low radiation energy absorption coefficient in radiation therapy. High doses of X-rays may lead to side effects in the surrounding normal tissues. In order to overcome the radio-resistance and improve the efficacy of radiotherapy based on the characteristics of the tumor microenvironment, the development of radiosensitizers has attracted much attention. In this study, a Janus ACSP nanoparticle (NP) was developed for chemodynamic therapy and radiosensitization. The reactive oxygen species generated by the Fenton-like reaction regulated the distribution of cell cycles from a radioresistant phase to a radio-sensitive phase. The high-Z element, Au, enhanced the production of hydroxyl radicals (•OH) under X-ray radiation, promoting DNA damage and cell apoptosis. The NP delayed DNA damage repair by interfering with certain proteins involved in the DNA repair signaling pathway. In vivo experiments demonstrated that the combination of the copper-ion-based Fenton-like reaction and low-dose X-ray radiation enhanced the effectiveness of radiotherapy, providing a novel approach for synergistic chemodynamic and radiosensitization therapy. This study provides valuable insights and strategies for the development and application of NPs in cancer treatment.

Enhancing X-Ray Sensitization with Multifunctional Nanoparticles.

In the progression of X-ray-based radiotherapy for the treatment of cancer, the incorporation of nanoparticles (NPs) has a transformative impact. This study investigates the potential of NPs, particularly those comprised of high atomic number elements, as radiosensitizers. This aims to optimize localized radiation doses within tumors, thereby maximizing therapeutic efficacy while preserving surrounding tissues. The multifaceted applications of NPs in radiotherapy encompass collaborative interactions with chemotherapeutic, immunotherapeutic, and targeted pharmaceuticals, along with contributions to photodynamic/photothermal therapy, imaging enhancement, and the integration of artificial intelligence technology. Despite promising preclinical outcomes, the paper acknowledges challenges in the clinical translation of these findings. The conclusion maintains an optimistic stance, emphasizing ongoing trials and technological advancements that bolster personalized treatment approaches. The paper advocates for continuous research and clinical validation, envisioning the integration of NPs as a revolutionary paradigm in cancer therapy, ultimately enhancing patient outcomes.

Ferroptosis: Frenemy of Radiotherapy.

Recently, it was established that ferroptosis, a type of iron-dependent regulated cell death, plays a prominent role in radiotherapy-triggered cell death. Accordingly, ferroptosis inducers attracted a lot of interest as potential radio-synergizing drugs, ultimately enhancing radioresponses and patient outcomes. Nevertheless, the tumor microenvironment seems to have a major impact on ferroptosis induction. The influence of hypoxic conditions is an area of interest, as it remains the principal hurdle in the field of radiotherapy. In this review, we focus on the implications of hypoxic conditions on ferroptosis, contemplating the plausibility of using ferroptosis inducers as clinical radiosensitizers. Furthermore, we dive into the prospects of drug repurposing in the domain of ferroptosis inducers and radiosensitizers. Lastly, the potential adverse effects of ferroptosis inducers on normal tissue were discussed in detail. This review will provide an important framework for subsequent ferroptosis research, ascertaining the feasibility of ferroptosis inducers as clinical radiosensitizers.

Radiotherapy Combined with a Radiosensitizer for Bacillus Calmette-Guérin-unresponsive Non-muscle-invasive Carcinoma In Situ Bladder Cancer: An Open-label, Single-arm, Multicenter, Phase 2 European Organisation for Research and Treatment of Cancer Trial.

Radical cystectomy with pelvic lymph node dissection and urinary diversion is the standard of care for patients with bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). However, many patients are unwilling or unable to undergo such major surgery associated with high morbidity and a negative impact on quality of life. Chemoradiotherapy is an established treatment option for muscle-invasive bladder cancer. However, it has not been investigated adequately in NMIBC until now. The European Organisation for Research and Treatment of Cancer (EORTC) 2235 study (NCT06310369) is designed as a multicenter, prospective, international, phase 2 trial of moderate hypofractionated radiotherapy combined with a radiosensitizer in BCG-unresponsive NMIBC patients with carcinoma in situ (CIS) who are not eligible for or declined to undergo radical cystectomy. Patients who have received nadofaragene firadenovec or TAR-200 are eligible. The primary endpoint is the 6-mo complete response (CR) rate defined by the absence of CIS proven by a control biopsy of the bladder. The secondary endpoints include overall survival, progression-free survival, durability of CR, grade 3-4 adverse events rate, patients' quality of life, and organ preservation rate. PATIENT SUMMARY: Intravesical instillation of bacillus Calmette-Guérin is the standard treatment of non-muscle-invasive, also coined as superficial, bladder cancer. In case the cancer recurs, even superficially, there is no other proven treatment than a radical cystectomy-the surgical removal of the bladder. Although the surgical technique has improved dramatically over the past few years, it remains contraindicated in patients with severe comorbidities. In addition, because it affects the quality of life, patients may reject this option. This study will assess the efficacy of external beam radiotherapy, a robust alternative to surgery in muscle-invasive bladder cancer. Radiotherapy will be administered 5 d a week for 4 wk. It will be associated with a "radiosensitizer," an intravenous or oral drug, during the radiotherapy treatment. The study will measure the proportion of patients remaining recurrence free at 6 mo and thereafter. It will also evaluate the safety of the treatment and its impact on quality of life.

Carbon-Iodine Polydiacetylene Nanofibers for Image-Guided Radiotherapy and Tumor-Microenvironment-Enhanced Radiosensitization.

Radiotherapy is a mainstay treatment used in clinics for locoregional therapy, although it still represents a great challenge to improve the sensitivity and accuracy of radiotherapy for tumors. Here, we report the conjugated polymer, polydiiododiacetylene (PIDA), with an iodine content of 84 wt %, as a highly effective computed tomography (CT) contrast agent and tumor microenvironment-responsive radiosensitizer. PIDA exhibited several key properties that contribute to the improvement of precision radiotherapy. The integrated PIDA nanofibers confined within the tumor envelope demonstrated amplified CT intensity and prolonged retention, providing an accurate calculation of dose distribution and precise radiation delivery for CT image-guided radiotherapy. Therefore, our strategy pioneers PIDA nanofibers as a bridge to cleverly connect a fiducial marker to guide accurate radiotherapy and a radiosensitizer to improve tumor sensitivity, thereby minimizing potential damage to surrounding tissues and facilitating on-demand therapeutic intervention in tumors.

A Novel Activatable Nanoradiosensitizer for Second Near-Infrared Fluorescence Imaging-Guided Safe-Dose Synergetic Chemo-Radiotherapy of Rheumatoid Arthritis.

The precise theranostics of rheumatoid arthritis (RA) remains a formidable challenge in clinical practice. Exploring novel applications of contemporary therapeutic approaches like chemo-radiotherapy is promising as a highly effective strategy for RA. Herein, a novel activatable nanoradiosensitizer-40 (denoted as IRnR-40) is developed, based on encapsulating the clinically approved drugs cisplatin (DDP) and indocyanine green (ICG) within a gelatin shell to achieve second near-infrared fluorescence (NIR-II FL) imaging-guided safe-dose synergetic chemo-radiotherapy. The high concentration of matrix metalloproteinase-9 (MMP-9) in the RA microenvironment plays a pivotal role in triggering the responsive degradation of IRnR-40, leading to the rapid release of functional molecules DDP and ICG. The released ICG serves the dual purpose of illuminating the inflamed joints to facilitate accurate target volume delineation for guiding radiotherapy, as well as acting as a real-time reporter for quantifying the release of DDP to monitor efficacy. Meanwhile, the released DDP achieves highly effective synergistic chemotherapy and radiosensitization for RA via the dual reactive oxygen species (ROS)-mediated mitochondrial apoptotic pathway. To sum up, this activatable nanoradiosensitizer IRnR-40 is believed to be the first attempt to achieve efficient NIR-II FL imaging-guided safe-dose chemo-radiotherapy for RA, which provides a new paradigm for precise theranostics of refractory benign diseases.