Radioactive hybrid semiconducting polymer nanoparticles for imaging-guided tri-modal therapy of breast cancer.

Due to the rapid progression and aggressive metastasis of breast cancer, its diagnosis and treatment remain a great challenge. The simultaneous inhibition of tumor growth and metastasis is necessary for breast cancer to obtain ideal therapeutic outcomes. We herein report the development of radioactive hybrid semiconducting polymer nanoparticles (SPNH) for imaging-guided tri-modal therapy of breast cancer. Two semiconducting polymers are used to form SPNH with a diameter of around 60 nm via nano-coprecipitation and they are also labeled with iodine-131 (131I) to enhance the imaging functions. The formed SPNH show good radiolabeling stability and excellent photodynamic and photothermal effects under 808 nm laser irradiation to produce singlet oxygen (1O2) and heat. Moreover, SPNH can generate 1O2 with ultrasound irradiation via their sonodynamic properties. After intravenous tail vein injection, SPNH can effectively accumulate in the subcutaneous 4T1 tumors of living mice as verified via fluorescence and single photon emission computed tomography (SPECT) imaging. With the irradiation of tumors using an 808 nm laser and US, SPNH mediate photodynamic therapy (PDT), photothermal therapy (PTT) and sonodynamic therapy (SDT) to kill tumor cells. Such a tri-modal therapy leads to an improved efficacy in inhibiting tumor growth and suppressing tumor metastasis compared to the sole SDT and combinational PDT-PTT. This study thus demonstrates the applications of SPNH to diagnose tumors and combine different therapies for effective breast cancer treatment.

Sono-Triggered Cascade Lactate Depletion by Semiconducting Polymer Nanoreactors for Cuproptosis-Immunotherapy of Pancreatic Cancer.

The high level of lactate in tumor microenvironment not only promotes tumor development and metastasis, but also induces immune escape, which often leads to failures of various tumor therapy strategies. We here report a sono-triggered cascade lactate depletion strategy by using semiconducting polymer nanoreactors (SPNLCu) for cancer cuproptosis-immunotherapy. The SPNLCu mainly contain a semiconducting polymer as sonosensitizer, lactate oxidase (LOx) conjugated via a reactive oxygen species (ROS)-cleavable linker and chelated Cu2+. Upon ultrasound (US) irradiation, the semiconducting polymer generates singlet oxygen (1O2) to cut ROS-cleavable linker to allow the release of LOx that catalyzes lactate depletion to produce hydrogen peroxide (H2O2). The Cu2+ will be reduced to Cu+ in tumor microenvironment, which reacts with the produced H2O2 to obtain hydroxyl radical (·OH) that further improves LOx release via destroying ROS-cleavable linkers. As such, sono-triggered cascade release of LOx achieves effective lactate depletion, thus relieving immunosuppressive roles of lactate. Moreover, the toxic Cu+ induces cuproptosis to cause immunogenic cell death (ICD) for activating antitumor immunological effect. SPNLCu are used to treat both subcutaneous and deep-tissue orthotopic pancreatic cancer with observably enhanced efficacy in restricting the tumor growths. This study thus provides a precise and effective lactate depletion tactic for cancer therapy.

Progressive Optimization of Lanthanide Nanoparticle Scintillators for Enhanced Triple-Activated Radioluminescence Imaging.

Lanthanide nanoparticle (LnNP) scintillators exhibit huge potential in achieving radionuclide-activated luminescence (radioluminescence, RL). However, their structure-activity relationship remains largely unexplored. Herein, progressive optimization of LnNP scintillators is presented to unveil their structure-dependent RL property and enhance their RL output efficiency. Benefiting from the favorable host matrix and the luminescence-protective effect of core-shell engineering, NaGdF4:15%Eu@NaLuF4 nanoparticle scintillators with tailored structures emerged as the top candidates. Living imaging experiments based on optimal LnNP scintillators validated the feasibility of laser-free continuous RL activated by clinical radiopharmaceuticals for tumor multiplex visualization. This research provides unprecedented insights into the rational design of LnNP scintillators, which would enable efficient energy conversion from Cerenkov luminescence, γ-radiation, and ß-electrons into visible photon signals, thus establishing a robust nanotechnology-aided approach for tumor-directed radio-phototheranostics.

A Computational and Chemical Design Strategy for Manipulating Glycan-Protein Recognition.

Glycans are complex biomolecules that encode rich information and regulate various biological processes, such as fertilization, host-pathogen binding, and immune recognition, through interactions with glycan-binding proteins. A key driving force for glycan-protein recognition is the interaction between the π electron density of aromatic amino acid side chains and polarized C─H groups of the pyranose (termed the CH-π interaction). However, the relatively weak binding affinity between glycans and proteins has hindered the application of glycan detection and imaging. Here, computational modeling and molecular dynamics simulations are employed to design a chemical strategy that enhances the CH-π interaction between glycans and proteins by genetically incorporating electron-rich tryptophan derivatives into a lectin PhoSL, which specifically recognizes core fucosylated N-linked glycans. This significantly enhances the binding affinity of PhoSL with the core fucose ligand and enables sensitive detection and imaging of core fucosylated glycans in vitro and in xenograft tumors in mice. Further, the study showed that this strategy is applicable to improve the binding affinity of GafD lectin for N-acetylglucosamine-containing glycans. The approach thus provides a general and effective way to manipulate glycan-protein recognition for glycoscience applications.

Dual-enzyme decorated semiconducting polymer nanoagents for second near-infrared photoactivatable ferroptosis-immunotherapy.

Enzymes provide a class of potential options to treat cancer, while the precise regulation of enzyme activities for effective and safe therapeutic actions has been poorly reported. Dual-enzyme decorated semiconducting polymer nanoagents for second near-infrared (NIR-II) photoactivatable ferroptosis-immunotherapy are reported in this study. Such nanoagents (termed SPHGA) consist of hemoglobin (Hb)-based semiconducting polymer (SP@Hb), adenosine deaminase (ADA) and glucose oxidase (GOx) with loadings in a thermal-responsive nanoparticle shell. NIR-II photoactivation of SPHGA results in the generation of heat to trigger on-demand releases of two enzymes (ADA and GOx) via destroying the thermal-responsive nanoparticle shells. In the tumor microenvironment, GOx oxidizes glucose to form hydrogen peroxide (H2O2), which promotes the Fenton reaction of iron in SP@Hb, resulting in an enhanced ferroptosis effect and immunogenic cell death (ICD). In addition, ADA degrades high-level adenosine to reverse the immunosuppressive microenvironment, thus amplifying antitumor immune responses. Via NIR-II photoactivatable ferroptosis-immunotherapy, SPHGA shows an improved effect to absolutely remove bilateral tumors and effectively suppress tumor metastases in subcutaneous 4T1 breast cancer models. This study presents a dual-enzyme-based nanoagent with controllable therapeutic actions for effective and precise cancer therapy.

Bevacizumab improved prognosis for advanced EGFR-mutant lung adenocarcinoma with brain metastasis receiving cerebral radiotherapy.

OBJECTIVE: This study aimed to determine whether the combined use of bevacizumab could improve overall survival (OS) in patients with brain metastasis (BM), epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) undergoing cerebral radiotherapy. MATERIALS AND METHODS: A total of 237 patients with EGFR-mutant lung adenocarcinoma and BM met the inclusion criteria for this retrospective study, including 102 patients in the bevacizumab treatment group and 135 in the non-bevacizumab group. The Kaplan-Meier method was used for survival analysis. Univariate and multivariate analyses were performed to identify EGFR-mutated BM prognostic factors for these patients. RESULTS: At the end of the last follow-up period, 176 patients (74.3%) had died, and the median overall survival (OS) was 34.2 months. We observed a significant difference in the median OS between the bevacizumab and non-bevacizumab groups (45.8 months vs 30.0 months, P < 0.0001). Among the 178 (75.1%) patients who received cerebral radiotherapy, the median OS of patients in the bevacizumab + cerebral radiotherapy group was 45.8 months versus 32.0 months in the non-bevacizumab + cerebral radiotherapy group, respectively (P = 0.0007). Patients treated with bevacizumab after cerebral radiotherapy had a longer median OS than patients treated with bevacizumab before cerebral radiotherapy (59.4 months vs 33.7 months, P = 0.0198). In the univariate analysis, smoking status, Lung-molGPA scores, and bevacizumab therapy showed correlations (HR = 1.450, P = 0.045; HR = 0.700, P = 0.023; HR = 0.499, P < 0.001). Multivariate analysis showed that bevacizumab therapy alone (hazard ratio [HR] = 0.514; P < 0.001) was independently associated with improved OS. CONCLUSION: In patients with BM from EGFR-mutated NSCLC, cerebral radiotherapy with bevacizumab markedly improved OS. This improvement was more evident after cerebral radiotherapy.

A proof-of-concept study on bioorthogonal-based pretargeting and signal amplify radiotheranostic strategy.

BACKGROUND: Radiotheranostics differs from the vast majority of other cancer therapies in its capacity for simultaneous imaging and therapy, and it is becoming more widely implemented. A balance between diagnostic and treatment requirements is essential for achieving effective radiotheranostics. Herein, we propose a proof-of-concept strategy aiming to address the profound differences in the specific requirements of the diagnosis and treatment of radiotheranostics. RESULTS: To validate the concept, we designed an s-tetrazine (Tz) conjugated prostate-specific membrane antigen (PSMA) ligand (DOTA-PSMA-Tz) for 68Ga or 177Lu radiolabeling and tumor radiotheranostics, a trans-cyclooctene (TCO) modified Pd@Au nanoplates (Pd@Au-PEG-TCO) for signal amplification, respectively. We then demonstrated this radiotheranostic strategy in the tumor-bearing mice with the following three-step procedures: (1) i.v. injection of the [68Ga]Ga-PSMA-Tz for diagnosis; (2) i.v. injection of the signal amplification module Pd@Au-PEG-TCO; (3) i.v. injection of the [177Lu]Lu-PSMA-Tz for therapy. Firstly, this strategy was demonstrated in 22Rv1 tumor-bearing mice via positron emission tomography (PET) imaging with [68Ga]Ga-PSMA-Tz. We observed significantly higher tumor uptake (11.5 ± 0.8%ID/g) with the injection of Pd@Au-PEG-TCO than with the injection [68Ga]Ga-PSMA-Tz alone (5.5 ± 0.9%ID/g). Furthermore, we validated this strategy through biodistribution studies of [177Lu]Lu-PSMA-Tz, with the injection of the signal amplification module, approximately five-fold higher tumor uptake of [177Lu]Lu-PSMA-Tz (24.33 ± 2.53% ID/g) was obtained when compared to [177Lu]Lu-PSMA-Tz alone (5.19 ± 0.26%ID/g) at 48 h post-injection. CONCLUSION: In summary, the proposed strategy has the potential to expand the toolbox of pretargeted radiotherapy in the field of theranostics.

Tumor-targeting polymer nanohybrids with amplified ROS generation for combined photodynamic and chemodynamic therapy.

Reactive oxygen species (ROS) generating strategies have been widely adopted for cancer therapy, but therapeutic efficacies are often low due to the complicated tumor microenvironment. In this study, we present the development of tumor-targeting polymer nanohybrids that amplify ROS generation by combining photodynamic therapy (PDT) and chemodynamic therapy (CDT) for cancer treatment. Such polymer nanohybrids contained three main components: a semiconducting polymer (SP) that acted as the photosensitizer for PDT, manganese dioxide (MnO2) that acted as the catalyst for CDT, and transferrin that mediated tumor targeting via binding to transferrin receptors overexpressed on the surface of tumor cells. The formed nanohybrids (TSM) showed obviously enhanced accumulation efficacy in tumor sites because of their targeting ability. In tumor sites, TSM produced singlet oxygen (1O2) under near-infrared (NIR) laser irradiation and a hydroxyl radical (˙OH) via reacting with hydrogen peroxide (H2O2), which resulted in amplified generation of ROS to achieve PDT/CDT combinational therapy. The growth of subcutaneous 4T1 tumors was remarkably inhibited via TSM-mediated treatment. In addition, this therapeutic efficacy could suppress tumor metastasis in the liver and lungs. This study presents a targeting hybrid nanoplatform to combine different ROS generating strategies for effective cancer therapy.

A continuously efficient O2-supplying strategy for long-term modulation of hypoxic tumor microenvironment to enhance long-acting radionuclides internal therapy.

Radionuclides internal radiotherapy (RIT) is a clinically powerful method for cancer treatment, but still poses unsatisfactory therapeutic outcomes due to the hypoxic characteristic of tumor microenvironment (TME). Catalase (CAT) or CAT-like nanomaterials can be used to enzymatically decompose TME endogenous H2O2 to boost TME oxygenation and thus alleviate the hypoxic level within tumors, but their effectiveness is still hindered by the short-lasting of hypoxia relief owing to their poor stability or degradability, thereby failing to match the long therapeutic duration of RIT. Herein, we proposed an innovative strategy of using facet-dependent CAT-like Pd-based two-dimensional (2D) nanoplatforms to continuously enhance RIT. Specifically, rationally designed 2D Pd@Au nanosheets (NSs) enable consistent enzymatic conversion of endogenous H2O2 into O2 to overcome hypoxia-induced RIT resistance. Furthermore, partially coated Au layer afford NIR-II responsiveness and moderate photothermal treatment that augmenting their enzymatic functionality. This approach with dual-effect paves the way for reshaping TME and consequently facilitating the brachytherapy ablation of cancer. Our work offers a significant advancement in the integration of catalytic nanomedicine and nuclear medicine, with the overarching goal of amplifying the clinical benefits of RIT-treated patients.

Dual-Targeting Biomimetic Semiconducting Polymer Nanocomposites for Amplified Theranostics of Bone Metastasis.

Bone metastasis is a type of metastatic tumors that involves the spreads of malignant tumor cells into skeleton, and its diagnosis and treatment remain a big challenge due to the unique tumor microenvironment. We herein develop osteoclast and tumor cell dual-targeting biomimetic semiconducting polymer nanocomposites (SPFeNOC ) for amplified theranostics of bone metastasis. SPFeNOC contain semiconducting polymer and iron oxide (Fe3 O4 ) nanoparticles inside core and surface camouflaged hybrid membrane of cancer cells and osteoclasts. The hybrid membrane camouflage enables their targeting to both metastatic tumor cells and osteoclasts in bone metastasis through homologous targeting mechanism, thus achieving an enhanced nanoparticle accumulation in tumors. The semiconducting polymer mediates near-infrared (NIR) fluorescence imaging and sonodynamic therapy (SDT), and Fe3 O4 nanoparticles are used for magnetic resonance (MR) imaging and chemodynamic therapy (CDT). Because both cancer cells and osteoclasts are killed synchronously via the combinational action of SDT and CDT, the vicious cycle in bone metastasis is broken to realize high antitumor efficacy. Therefore, 4T1 breast cancer-based bone metastasis can be effectively detected and cured by using SPFeNOC as dual-targeting theranostic nanoagents. This study provides an unusual biomimetic nanoplatform that simultaneously targets osteoclasts and cancer cells for amplified theranostics of bone metastasis.

Dual-Programmable Semiconducting Polymer NanoPROTACs for Deep-Tissue Sonodynamic-Ferroptosis Activatable Immunotherapy.

Proteolysis-targeting chimeras (PROTACs) can provide promising opportunities for cancer treatment, while precise regulation of their activities remains challenging to achieve effective and safe therapeutic outcomes. A semiconducting polymer nanoPROTAC (SPNFeP ) is reported that can achieve ultrasound (US) and tumor microenvironment dual-programmable PROTAC activity for deep-tissue sonodynamic-ferroptosis activatable immunotherapy. SPNFeP is formed through a nano-precipitation of a sonodynamic semiconducting polymer, a ferroptosis inducer, and a newly synthesized PROTAC molecule. The semiconducting polymers work as sonosensitizers to produce singlet oxygen (1 O2 ) via sonodynamic effect under US irradiation, and ferroptosis inducers react with intratumoral hydrogen peroxide (H2 O2 ) to generate hydroxyl radical (·OH). Such a dual-programmable reactive oxygen species (ROS) generation not only triggers ferroptosis and immunogenic cell death (ICD), but also induces on-demand activatable delivery of PROTAC molecules into tumor sites. The effectively activated nanoPROTACs degrade nicotinamide phosphoribosyl transferase (NAMPT) to suppress tumor infiltration of myeloid-derived suppressive cells (MDSCs), thus promoting antitumor immunity. In such a way, SPNFeP mediates sonodynamic-ferroptosis activatable immunotherapy for entirely inhibiting tumor growths in both subcutaneous and 2-cm tissue-covered deep tumor mouse models. This study presents a dual-programmable activatable strategy based on PROTACs for effective and precise cancer combinational therapy.

Cerenkov radiation-mediated in situ activation of silicon nanocrystals for NIR optical imaging.

Cerenkov radiation from radiopharmaceuticals (18F-FDG) serves as an internal light source to excite UV-responsive silicon nanocrystals for near-infrared luminescence imaging that offers deeper tissue penetration and high signal-to-noise ratio.

Drug-loaded hybrid hydrogels for sonodynamic-chemodyanmic therapy and tumor metastasis suppression.

Introduction: Although various therapies have been adopted to treat cancer, metastasis of tumor cells still is a big challenge that compromises therapeutic benefits. Methods: We herein report an injectable drug-loaded hybrid hydrogel that can achieve sonodynamic therapy (SDT) and chemodyanmic therapy (CDT) combined action and suppression of tumor metastasis. This alginate (ALG)-based hydrogel (termed as AMPS) contains manganese dioxide (MnO2) nanoparticles as the CDT agents, an organic polymer as the sonosensitizer, and a SIS3 drug as metastasis inhibitor. Results: AMPS is formed via the chelation of ALG by Ca2+ in tumor microenvironment, in which MnO2 nanoparticles mediate CDT via Fenton-like reaction and the organic polymers enable SDT under ultrasound (US) irradiation by generating singlet oxygen (1O2), allowing for combinational action of CDT and SDT. In addition, SIS3 is released from AMPS hydrogels to inhibit the metastasis of tumor cells. As such, the AMPS enables a combinational action of SDT and CDT to greatly inhibit the growths of subcutaneous tumors in living mice and also completely suppress the tumor metastasis in lungs and livers. Conclusion: This study thus offers a hybrid hydrogel platform for combinational therapy and metastasis suppression simultaneously.

Sono-Activatable Semiconducting Polymer Nanoreshapers Multiply Remodel Tumor Microenvironment for Potent Immunotherapy of Orthotopic Pancreatic Cancer.

Due to the complicated tumor microenvironment that compromises the efficacies of various therapies, the effective treatment of pancreatic cancer remains a big challenge. Sono-activatable semiconducting polymer nanoreshapers (SPNDN H) are constructed to multiply remodel tumor microenvironment of orthotopic pancreatic cancer for potent immunotherapy. SPNDN H contain a semiconducting polymer, hydrogen sulfide (H2 S) donor, and indoleamine 2,3-dioxygenase (IDO) inhibitor (NLG919), which are encapsulated by singlet oxygen (1 O2 )-responsive shells with modification of hyaluronidase (HAase). After accumulation in orthotopic pancreatic tumor sites, SPNDN H degrade the major content of tumor microenvironment hyaluronic acid to promote nanoparticle enrichment and immune cell infiltration, and also release H2 S to relieve tumor hypoxia via inhibiting mitochondrion functions. Moreover, the relieved hypoxia enables amplified sonodynamic therapy (SDT) under ultrasound (US) irradiation with generation of 1 O2 , which leads to immunogenic cell death (ICD) and destruction of 1 O2 -responsive components to realize sono-activatable NLG919 release for reversing IDO-based immunosuppression. Through such a multiple remodeling mechanism, a potent antitumor immunological effect is triggered after SPNDN H-based treatment. Therefore, the growths of orthotopic pancreatic tumors in mouse models are almost inhibited and tumor metastases are effectively restricted. This study offers a sono-activatable nanoplatform to multiply remodel tumor microenvironment for effective and precise immunotherapy of deep-tissue orthotopic tumors.

Near-infrared light-activated ROS generation using semiconducting polymer nanocatalysts for photodynamic-chemodynamic therapy.

Chemodynamic therapy (CDT) is an emerging treatment strategy for cancer, but the low therapeutic efficacy and potential side effects still limit its applications. In this study, we report a semiconducting polymer nanocatalyst (PGFe) that can generate reactive oxygen species (ROS) only upon near-infrared (NIR) light-activation for photodynamic therapy (PDT)-synergized CDT. Such PGFe consists of a semiconducting polymer as a photosensitizer, iron oxide (Fe3O4) nanoparticles as CDT agents, and glucose oxidase (GOx), all of which are loaded into a singlet oxygen (1O2)-responsive nanocarrier. Under NIR laser irradiation, PGFe produces 1O2 through a photosensitizer-mediated PDT effect, and the produced 1O2 destroys the 1O2-responsive nanocarriers, leading to controlled releases of Fe3O4 nanoparticles and GOx. In a tumor microenvironment, GOx catalyzes glucose degradation to form hydrogen peroxide (H2O2), and thus the CDT effect of Fe3O4 nanoparticles is greatly improved. As such, an amplified ROS level in tumor cells is obtained by PGFe to induce cell death. PGFe can be utilized to treat subcutaneous 4T1 tumors, observably inhibiting the tumor growth and suppressing lung and liver metastasis. This study thus provides a NIR light-activated ROS generation strategy for precise and effective treatments of tumors.

Activatable Semiconducting Polymer Nanoinducers Amplify Oxidative Damage via Sono-Ferroptosis for Synergistic Therapy of Bone Metastasis.

Bone metastases are secondary malignant tumors that commonly occur after the spread of advanced cancer cells. We herein report the activatable semiconducting polymer nanoinducers (ASPNFP) that can amplify oxidative damage via sono-ferroptosis for bone metastasis treatment. ASPNFP are constructed by encapsulating plasma amine oxidase-based semiconducting polymer nanoparticles (SPNP) and Fe3O4 nanoparticles into singlet oxygen (1O2)-responsive nanocarriers. ASPNFP generate 1O2 under ultrasound (US) irradiation via a sonodynamic effect to destroy the stability of 1O2-responsive nanocarriers, allowing US-triggered releases of SPNP and Fe3O4 nanoparticles. SPNP decompose polyamines in tumor cells to produce acrolein and hydrogen peroxide (H2O2), in which H2O2 promotes Fenton reaction mediated by Fe3O4 nanoparticles for inducing enhanced ferroptosis and generation of hydroxyl radicals (•OH). The generated acrolein, 1O2, and •OH can simultaneously amplify the oxidative damage. ASPNFP thus mediate an amplified sono-ferroptosis effect to inhibit the growth of bone metastasis and restrict tumor metastasis.

Prodrug-loaded semiconducting polymer hydrogels for deep-tissue sono-immunotherapy of orthotopic glioblastoma.

Although immunotherapy has achieved great success in the treatment of a variety of tumors, its efficacy for glioblastoma (GBM) is still limited. Both the immunosuppressive tumor microenvironment (TME) and poor penetration of immunotherapeutic agents into tumors contributed to the poor anti-glioma immunity. Herein, we develop an injectable prodrug-loaded hydrogel delivery system with sono-activatable properties for sonodynamic therapy (SDT)-triggered immunomodulation for GBM treatment. The prodrug alginate hydrogels (APN), which contain semiconducting polymer nanoparticles (SPNs) and the NLG919 prodrug linked by singlet oxygen (1O2)-cleavable linkers, are in situ formed via coordination of alginate solution with Ca2+ in the TME. SPNs serve as sonosensitizers to produce 1O2 upon ultrasound (US) irradiation for SDT. The generated 1O2 not only induce immunogenic cell death, but also break 1O2-cleavable linkers to precisely activate the NLG919 prodrug. Antitumor immunity is significantly amplified due to the reversal of immunosuppression mediated by indolamine 2,3-dioxygenase-dependent tryptophan metabolism. This smart prodrug hydrogel platform potently inhibits tumor growth in orthotopic glioma-bearing mice. Collectively, this work provides a sono-activatable hydrogel platform for precise sono-immunotherapy against GBM.

Identification of VPS34-PI(3)P-FEN1-mediated DNA repair pathway as a potential drug target to overcome chemoresistance.

Intrinsic or acquired chemoresistance represents a major obstacle in cancer treatment. Multiple mechanisms can contribute to cancer cells' resistance to chemotherapy. Among them, an aberrantly strengthened DNA repair mechanism is responsible for a large proportion of drug resistance to alkylating agents and radiation therapy. In cancer cells, damping overactivated DNA repair system can overcome survival advantages conferred by chromosomal translocations or mutations and lead to cytostatic effects or cytotoxic. Therefore, selectively targeting DNA repair system in cancer cells holds promise for overcoming chemoresistance. In this study, we revealed that the endonuclease Flap Endonuclease 1 (FEN1), essential for DNA replication and repair, directly interacts with phosphatidylinositol 3-phosphate [PI(3)P], and FEN1-R378 is the primary PI(3)P-binding site. PI(3)P-binding deficient FEN1 mutant (FEN1-R378A) cells exhibited abnormal chromosomal structures and were hypersensitized to DNA damage. The PI(3)P-mediated FEN1 functionality was essential for repairing DNA damages caused by multiple mechanisms. Furthermore, VPS34, the major PI(3)P synthesizing enzyme, was negatively associated with patients' survival in various cancer types, and VPS34 inhibitors significantly sensitized chemoresistant cancer cells to genotoxic agents. These findings open up an avenue for counteracting chemoresistance by targeting VPS34-PI(3)P-mediated DNA repair pathway, and call for assessing the efficacy of this strategy in patients suffering from chemoresistance-mediated cancer recurrence in clinical trials.

Augmenting Immunogenic Cell Death and Alleviating Myeloid-Derived Suppressor Cells by Sono-Activatable Semiconducting Polymer Nanopartners for Immunotherapy.

Inducing immunogenic cell death (ICD) by sonodynamic therapy (SDT) is promising for cancer immunotherapy, which however is inefficient due to oxygen depletion that compromises SDT effect and mediates recruitment of immunosuppressive myeloid-derived suppressor cells (MDSCs). The fabrication of sono-activatable semiconducting polymer nanopartners (SPNTi ) to simultaneously augment ICD and alleviate MDSCs for immunotherapy is reported. A sonodynamic semiconducting polymer, hydrophobic hypoxia-responsive tirapazamine (TPZ)-conjugate, and MDSC-targeting drug (ibrutinib) are encapsulated inside such SPNTi with surface shell of a singlet oxygen (1 O2 )-cleavable amphiphilic polymer. TPZ and ibrutinib serve as drug partners to enlarge immunotherapeutic effect. Upon sono-activation, SPNTi generate 1 O2 to break 1 O2 -cleavable polymers for in situ liberations of TPZ-conjugate and ibrutinib in tumor sites, and oxygen is consumed to create severe hypoxic tumor microenvironment, in which, TPZ-conjugate is activated for augmenting ICD action, while ibrutinib alleviates MDSCs for promoting antitumor immunological effect. In a bilateral tumor mouse model, SPNTi -mediated sono-activatable immunotherapy results in growth restraints of primary and distant tumors and noteworthy precaution of tumor metastases. This study thus provides a sono-activatable immunotherapeutic strategy with high precision and safety for cancer via overcoming post-treatment hypoxia and targeting MDSCs.

Activatable Semiconducting Polymer Pro-nanomodulators for Deep-Tissue Sono-immunotherapy of Orthotopic Pancreatic Cancer.

Immunotherapy has provided a promising modality for cancer treatment, while it often has the issues of limited response rates and potential off-target side effects in clinical practice. We herein report the construction of semiconducting polymer pro-nanomodulators (SPpMs) with ultrasound (US)-mediated activatable pharmacological actions for deep-tissue sono-immunotherapy of orthotopic pancreatic cancer. Such SPpMs consist of a sonodynamic semiconducting polymer backbone grafted with poly(ethylene glycol) chains linked with two immunomodulators (a programmed death-ligand 1 blocker and an indoleamine 2,3-dioxygenase inhibitor) via a singlet oxygen (1 O2 )-cleavable segment. In view of the excellent sonodynamic property of the semiconducting polymer core, SPpMs enable effective generation of 1 O2 under US treatment, even in a deep-tissue depth up to 12 cm. The generated 1 O2 not only ablates tumors via a sonodynamic effect and induces immunogenic cell death, but also destroys the 1 O2 -cleavable segments to allow in situ release of immunomodulators in tumors. This synergetic action results in boosted antitumor immune response via reversing two tumor immunosuppressive pathways. As such, SPpMs mediate deep-tissue sono-immunotherapy to completely eradicate orthotopic pancreatic cancer and effectively prevent tumor metastasis. Moreover, such an immune activation reduces the possibility of immune-related adverse events. This study thus provides a smart activatable nanoplatform for precise immunotherapy of deep-seated tumors.