Glucose-G protein signaling plays a crucial role in tomato resilience to high temperature and elevated CO2.

Global climate change is accompanied by carbon dioxide (CO2) enrichment and high-temperature stress; however, how plants adapt to the combined environments and the underlying mechanisms remain largely unclear. Here, we show that elevated CO2 alleviated plant sensitivity to high-temperature stress, with significantly increased apoplastic glucose (Glc) levels in tomato (Solanum lycopersicum) leaves. Exogenous Glc treatment enhanced tomato resilience to high-temperature stress under ambient CO2 conditions. Cell-based biolayer interferometry, subcellular localization, and Split-Luc assays revealed that Glc bound to tomato regulator of G protein signaling 1 (RGS1) and induced RGS1 endocytosis and thereby RGS1-G protein α subunit (GPA1) dissociation in a concentration-dependent manner. Using rgs1 and gpa1 mutants, we found that RGS1 negatively regulated thermotolerance and was required for elevated CO2-Glc-induced thermotolerance. GPA1 positively regulated the elevated CO2-Glc-induced thermotolerance. Transcriptome and chlorophyll fluorescence parameter analysis further revealed that GPA1 integrated photosynthesis- and photoprotection-related mechanisms to regulate thermotolerance. These results demonstrate that Glc-RGS1-GPA1 signaling plays a crucial role in the elevated CO2-induced thermotolerance in tomato. This information enhances our understanding of the Glc-G protein signaling function in stress resilience in response to global climate change and will be helpful for genetic engineering approaches to improve plant resilience.

Self-Adjuvanting Polyguanidine Nanovaccines for Cancer Immunotherapy.

Tapping into the innate immune system's power, nanovaccines can induce tumor-specific immune responses, which is a promising strategy in cancer immunotherapy. However, traditional vaccine design, requiring simultaneous loading of antigens and adjuvants, is complex and poses challenges for mass production. Here, we developed a tumor nanovaccine platform that integrates adjuvant functions into the delivery vehicle, using branched polyguanidine (PolyGu) nanovaccines. These nanovaccines were produced by modifying polyethylenimine (PEI) with various guanidine groups, transforming PEI's cytotoxicity into innate immune activation. The PolyGu nanovaccines based on poly(phenyl biguanidine ) (Poly-PBG) effectively stimulated dendritic cells, promoted their maturation via the TLR4 and NLRP3 pathways, and displayed robust in vivo immune activity. They significantly inhibited tumor growth and extended mouse survival. The PolyGu also showed promise for constructing more potent mRNA-based nanovaccines, offering a platform for personalized cancer vaccine. This work advances cancer immunotherapy toward potential clinical application by introducing a paradigm for developing self-adjuvanting nanovaccines.

Phytosulfokine promotes fruit ripening and quality via phosphorylation of transcription factor DREB2F in tomato.

Phytosulfokine (PSK), a plant peptide hormone with a wide range of biological functions, is recognized by its receptor PHYTOSULFOKINE RECEPTOR 1 (PSKR1). Previous studies have reported that PSK plays important roles in plant growth, development, and stress responses. However, the involvement of PSK in fruit development and quality formation remains largely unknown. Here, using tomato (Solanum lycopersicum) as a research model, we show that exogenous application of PSK promotes the initiation of fruit ripening and quality formation, while these processes are delayed in pskr1 mutant fruits. Transcriptomic profiling revealed that molecular events and metabolic pathways associated with fruit ripening and quality formation are affected in pskr1 mutant lines and transcription factors are involved in PSKR1-mediated ripening. Yeast screening further identified that DEHYDRATION-RESPONSIVE ELEMENT BINDING PROTEIN 2F (DREB2F) interacts with PSKR1. Silencing of DREB2F delayed the initiation of fruit ripening and inhibited the promoting effect of PSK on fruit ripening. Moreover, the interaction between PSKR1 and DREB2F led to phosphorylation of DREB2F. PSK improved the efficiency of DREB2F phosphorylation by PSKR1 at the tyrosine-30 site, and the phosphorylation of this site increased the transcription level of potential target genes related to the ripening process and functioned in promoting fruit ripening and quality formation. These findings shed light on the involvement of PSK and its downstream signaling molecule DREB2F in controlling climacteric fruit ripening, offering insights into the regulatory mechanisms governing ripening processes in fleshy fruits.

An in vitro-transcribed circular RNA targets the mitochondrial inner membrane cardiolipin to ablate EIF4G2+/PTBP1+ pan-adenocarcinoma.

In vitro-transcribed (IVT) mRNA has arisen as a rapid method for the production of nucleic acid drugs. Here, we have constructed an oncolytic IVT mRNA that utilizes human rhinovirus type 2 (HRV2) internal ribosomal entry sites (IRESs) to selectively trigger translation in cancer cells with high expression of EIF4G2 and PTBP1. The oncolytic effect was provided by a long hGSDMDc .825 T>A/c.884 A>G-F1LCT mutant mRNA sequence with mitochondrial inner membrane cardiolipin targeting toxicity that triggers mitophagy. Utilizing the permuted intron-exon (PIE) splicing circularization strategy and lipid nanoparticle (LNP) encapsulation reduced immunogenicity of the mRNA and enabled delivery to eukaryotic cells in vivo. Engineered HRV2 IRESs-GSDMDp.D275E/E295G-F1LCT circRNA-LNPs (GSDMDENG circRNA) successfully inhibited EIF4G2+/PTBP1+ pan-adenocarcinoma xenografts growth. Importantly, in a spontaneous tumor model with abnormal EIF4G2 and PTBP1 caused by KRAS G12D mutation, GSDMDENG circRNA significantly prevented the occurrence of pancreatic, lung and colon adenocarcinoma, improved the survival rate and induced persistent KRAS G12D tumor antigen-specific cytotoxic T lymphocyte responses.

Biomimetic nanovaccine-mediated multivalent IL-15 self-transpresentation (MIST) for potent and safe cancer immunotherapy.

Cytokine therapy, involving interleukin-15 (IL-15), is a promising strategy for cancer immunotherapy. However, clinical application has been limited due to severe toxicity and the relatively low immune response rate, caused by wide distribution of cytokine receptors, systemic immune activation and short half-life of IL-15. Here we show that a biomimetic nanovaccine, developed to co-deliver IL-15 and an antigen/major histocompatibility complex (MHC) selectively targets IL-15 to antigen-specific cytotoxic T lymphocytes (CTL), thereby reducing off-target toxicity. The biomimetic nanovaccine is composed of cytomembrane vesicles, derived from genetically engineered dendritic cells (DC), onto which IL-15/IL-15 receptor α (IL-15Rα), tumor-associated antigenic (TAA) peptide/MHC-I, and relevant costimulatory molecules are simultaneously anchored. We demonstrate that, in contrast to conventional IL-15 therapy, the biomimetic nanovaccine with multivalent IL-15 self-transpresentation (biNV-IL-15) prolonged blood circulation of the cytokine with an 8.2-fold longer half-life than free IL-15 and improved the therapeutic window. This dual targeting strategy allows for spatiotemporal manipulation of therapeutic T cells, elicits broad spectrum antigen-specific T cell responses, and promotes cures in multiple syngeneic tumor models with minimal systemic side effects.

Gas therapy potentiates aggregation-induced emission luminogen-based photoimmunotherapy of poorly immunogenic tumors through cGAS-STING pathway activation.

The immunologically "cold" microenvironment of triple negative breast cancer results in resistance to current immunotherapy. Here, we reveal the immunoadjuvant property of gas therapy with cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation to augment aggregation-induced emission (AIE)-active luminogen (AIEgen)-based photoimmunotherapy. A virus-mimicking hollow mesoporous tetrasulfide-doped organosilica is developed for co-encapsulation of AIEgen and manganese carbonyl to fabricate gas nanoadjuvant. As tetra-sulfide bonds are responsive to intratumoral glutathione, the gas nanoadjuvant achieves tumor-specific drug release, promotes photodynamic therapy, and produces hydrogen sulfide (H2S). Upon near-infrared laser irradiation, the AIEgen-mediated phototherapy triggers the burst of carbon monoxide (CO)/Mn2+. Both H2S and CO can destroy mitochondrial integrity to induce leakage of mitochondrial DNA into the cytoplasm, serving as gas immunoadjuvants to activate cGAS-STING pathway. Meanwhile, Mn2+ can sensitize cGAS to augment STING-mediated type I interferon production. Consequently, the gas nanoadjuvant potentiates photoimmunotherapy of poorly immunogenic breast tumors in female mice.

Activatable NIR-II Photothermal Lipid Nanoparticles for Improved Messenger RNA Delivery.

Endosomal escape remains a central issue limiting the high protein expression of mRNA therapeutics. Here, we present second near-infrared (NIR-II) lipid nanoparticles (LNPs) containing pH activatable NIR-II dye conjugated lipid (Cy-lipid) for potentiating mRNA delivery efficiency via a stimulus-responsive photothermal-promoted endosomal escape delivery (SPEED) strategy. In acidic endosomal microenvironment, Cy-lipid is protonated and turns on NIR-II absorption for light-to-heat transduction mediated by 1064 nm laser irradiation. Then, the heat-promoted LNPs morphology change triggers rapid escape of NIR-II LNPs from the endosome, allowing about 3-fold enhancement of enhanced green fluorescent protein (eGFP) encoding mRNA translation capacity compared to the NIR-II light free group. In addition, the bioluminescence intensity induced by delivered luciferase encoding mRNA in the mouse liver region shows positive correlation with incremental radiation dose, indicating the validity of the SPEED strategy.

Materials engineering strategies for cancer vaccine adjuvant development.

Cancer vaccines have emerged as a powerful new tool for cancer immunotherapy. Adjuvants are vaccine ingredients that enhance the strength, velocity, and duration of the immune response. The success of adjuvants in achieving stable, safe, and immunogenic cancer vaccines has generated enthusiasm for adjuvant development. Specifically, advances in materials science are providing insights into the rational design of vaccine adjuvants for topical cancer immunotherapy. Here, we outline the current state of materials engineering strategies, including those based on molecular adjuvants, polymers/lipids, inorganic nanoparticles, and bio-derived materials, for adjuvant development. We also elaborate on how these engineering strategies and the physicochemical features of the materials involved influence the effects of adjuvants.

Exosomal STIMATE derived from type II alveolar epithelial cells controls metabolic reprogramming of tissue-resident alveolar macrophages.

Background: Complete abolition of alveolar epithelial cells (AECs) is characteristic of end-stage lung disease. Transplantation therapy of type II AECs (AEC-IIs) or AEC-IIs-derived exosomes (ADEs) have been proposed as a means of repairing injury and preventing fibrosis. However, the mechanism by which ADEs balances airway immunity and alleviates damage and fibrosis remains unknown. Methods: We investigated STIM-activating enhancer-positive ADEs (STIMATE+ ADEs) in the lung of 112 ALI/ARDS and 44 IPF patients, and observed the correlation between STIMATE+ ADEs and subpopulation proportion and metabolic status of tissue-resident alveolar macrophages (TRAMs). We constructed the conditional knockout mice STIMATE sftpc , in which STIMATE was specifically knocked out in mouse AEC-IIs and observed the effects of STIMATE+ ADEs deficiency on disease progression, immune selection and metabolic switching of TRAMs. We constructed a BLM-induced AEC-IIs injury model to observe the salvage treatment of damage/fibrosis progression with STIMATE+ ADEs supplementation. Results: In clinical analysis, the distinct metabolic phenotypes of AMs in ALI/ARFS and IPF were significantly perturbed by STIMATE+ ADEs. The immune and metabolic status of TRAMs in the lungs of STIMATE sftpc mice was imbalanced, resulting in spontaneous inflammatory injury and respiratory disorders. STIMATE+ ADEs are taken up by tissue-resident alveolar macrophages TRAMs to regulate high Ca2+ responsiveness and long-term Ca2+ signal transduction, which maintains M2-like immunophenotype and metabolism selection. This involves calcineurin (CaN)-PGC-1α pathway mediated mitochondrial biogenesis and mtDNA coding. In a bleomycin-induced mouse fibrosis model, supplementation with inhaled STIMATE+ ADEs lessened early acute injury, prevented advanced fibrosis, alleviated ventilatory impairment and reduced mortality.

Molecularly self-fueled nano-penetrator for nonpharmaceutical treatment of thrombosis and ischemic stroke.

Thrombotic cerebro-cardiovascular diseases are the leading causes of disability and death worldwide. However, current drug therapeutics are compromised by narrow therapeutic windows, unsatisfactory thrombolysis effects, severe bleeding events, and high recurrence rates. In this study, we exploit a self-propelling nano-penetrator with high fuel loading and controllable motion features, which is molecularly co-assembled using a photothermal photosensitizer (DiR) and a photothermal-activable NO donor (BNN6). The precisely engineered nano-penetrator of the BNN6-DiR fuel pair shows distinct advantages in terms of NO productivity and autonomous motion under laser irradiation. In animal models of artery/vein thrombosis and acute ischemic stroke, the self-fueled nano-penetrator enables self-navigated thrombus-homing accumulation, self-propelled clot deep penetration, fluorescence image-guided photothermal/mechanical thrombolysis, and NO-mediated prevention of thrombosis recurrence and acute ischemic stroke salvage. As expected, the molecularly self-fueled nano-penetrator displayed favorable therapeutic outcomes without bleeding risk compared to the clinically available thrombolytic drug. This study offers a facile, safe, and effective nonpharmaceutical modality towards the clinical treatment of thrombosis and ischemic stroke.

Elaborately engineering of a dual-drug co-assembled nanomedicine for boosting immunogenic cell death and enhancing triple negative breast cancer treatment.

Pure drug-assembled nanosystem provides a facile and promising solution for simple manufacturing of nanodrugs, whereas a lack of understanding of the underlying assembly mechanism and the inefficient and uncontrollable drug release still limits the development and application of this technology. Here, a simple and practical nanoassembly of DOX and DiR is constructed on basis of their co-assembly characteristics. Multiple interaction forces are found to drive the co-assembly process. Moreover, DOX release from the nanoassembly can be well controlled by the acidic tumor microenvironment and laser irradiation, resulting in favorable delivery efficiency of DiR and DOX in vitro and in vivo. As expected, the nanoassembly with high therapeutic safety completely eradicated the mice triple negative breast cancer cells (4T1) on BALB/c mice, owing to synergistic chemo-photothermal therapy. More interestingly, DiR and DOX synergistically induce immunogenic cell death (ICD) of tumor cells after treatment, enabling the mice to acquire immune memory against tumor growth and recurrence. Such a facile nanoassembly technique provides a novel multimodal cancer treatment platform of chemotherapy/phototherapy/immunotherapy.

Elaborately Engineering a Self-Indicating Dual-Drug Nanoassembly for Site-Specific Photothermal-Potentiated Thrombus Penetration and Thrombolysis.

Thrombotic cardio-cerebrovascular diseases seriously threaten human health. Currently, conventional thrombolytic treatments are challenged by the low utilization, inferior thrombus penetration, and high off-target bleeding risks of most thrombolytic drugs, resulting in unsatisfactory treatment outcomes. Herein, it is proposed that these challenges can be overcome by precisely integrating the conventional thrombolytic strategy with photothermal therapy. After co-assembly engineering optimization, a fibrin-targeting peptide-decorated nanoassembly of DiR (a photothermal probe) and ticagrelor (TGL, an antiplatelet drug) is prepared for thrombus-homing delivery, abbreviated as FT-DT NPs. The elaborately engineered nanoassembly shows multiple advantages, including simple preparation with high drug co-loading capacity, synchronous delivery of two drugs with long systemic circulation, thrombus-targeted accumulation with self-indicating function, as well as photothermal-potentiated thrombus penetration and thrombolysis with high therapeutic efficacy. As expected, FT-DT NPs not only show bright fluorescence signals in the embolized vessels, but also perform photothermal/antiplatelet synergistic thrombolysis in vivo. This study offers a simple and versatile co-delivery nanoplatform for imaging-guided photothermal/antiplatelet dual-modality thrombolysis.

Pure photosensitizer-driven nanoassembly with core-matched PEGylation for imaging-guided photodynamic therapy.

Pure drug-assembled nanomedicines (PDANs) are currently under intensive investigation as promising nanoplatforms for cancer therapy. However, poor colloidal stability and less tumor-homing ability remain critical unresolved problems that impede their clinical translation. Herein, we report a core-matched nanoassembly of pyropheophorbide a (PPa) for photodynamic therapy (PDT). Pure PPa molecules are found to self-assemble into nanoparticles (NPs), and an amphiphilic PEG polymer (PPa-PEG2K) is utilized to achieve core-matched PEGylating modification via the π‒π stacking effect and hydrophobic interaction between the PPa core and the PPa-PEG2K shell. Compared to PCL-PEG2K with similar molecular weight, PPa-PEG2K significantly increases the stability, prolongs the systemic circulation and improves the tumor-homing ability and ROS generation efficiency of PPa-nanoassembly. As a result, PPa/PPa-PEG2K NPs exert potent antitumor activity in a 4T1 breast tumor-bearing BALB/c mouse xenograft model. Together, such a core-matched nanoassembly of pure photosensitizer provides a new strategy for the development of imaging-guided theragnostic nanomedicines.

Investigating the crucial roles of aliphatic tails in disulfide bond-linked docetaxel prodrug nanoassemblies.

Disulfide bond-bridging strategy has been extensively utilized to construct tumor specificity-responsive aliphatic prodrug nanoparticles (PNPs) for precise cancer therapy. Yet, there is no research shedding light on the impacts of the saturation and cis-trans configuration of aliphatic tails on the self-assembly capacity of disulfide bond-linked prodrugs and the in vivo delivery fate of PNPs. Herein, five disulfide bond-linked docetaxel-fatty acid prodrugs are designed and synthesized by using stearic acid, elaidic acid, oleic acid, linoleic acid and linolenic acid as the aliphatic tails, respectively. Interestingly, the cis-trans configuration of aliphatic tails significantly influences the self-assembly features of prodrugs, and elaidic acid-linked prodrug with a trans double bond show poor self-assembly capacity. Although the aliphatic tails have almost no effect on the redox-sensitive drug release and cytotoxicity, different aliphatic tails significantly influence the chemical stability of prodrugs and the colloidal stability of PNPs, thus affecting the in vivo pharmacokinetics, biodistribution and antitumor efficacy of PNPs. Our findings illustrate how aliphatic tails affect the assembly characteristic of disulfide bond-linked aliphatic prodrugs and the in vivo delivery fate of PNPs, and thus provide theoretical basis for future development of disulfide bond-bridged aliphatic prodrugs.

Zwitterion-Driven Shape Program of Prodrug Nanoassemblies with High Stability, High Tumor Accumulation, and High Antitumor Activity.

Prodrug nanoassemblies have emerged as a promising platform for the delivery of anticancer drugs. PEGylation is a "gold standard" to improve colloidal stability and pharmacokinetics of nanomedicines. However, the clinical application of PEG materials is challenged by in vivo oxidative degradation and immunogenicity. Rational design of advanced biomaterials for the surface modification of nanomedicines is the hot spot of research. Here, a zwitterionic sulfobetaine surfactant is constructed as a novel surface modifier to coassemble with 10-hydroxycamptothecin-linoleic acid conjugate, with the classical PEGylated material as control. Interestingly, both the type and ratio of surfactants have profound impacts on the molecular mechanisms of the assembly of prodrugs, thereby affecting the pharmaceutical properties. Compared with PEGylated spherical prodrug nanoassemblies, zwitterion-modified prodrug nanoassemblies have distinct rod shape and superhydrophilic surface, and exhibit potent antitumor activity due to the combination of multiple advantages in terms of colloidal stability, cellular uptake, and pharmacokinetics. The findings illustrate the crucial role of zwitterionic surfactants as the surface modifier in the determination of in vivo fate of the prodrug nanoassemblies, and pave the way for the development of advanced nanomedicines.

Molecularly engineered carrier-free co-delivery nanoassembly for self-sensitized photothermal cancer therapy.

BACKGROUND: Photothermal therapy (PTT) has been extensively investigated as a tumor-localizing therapeutic modality for neoplastic disorders. However, the hyperthermia effect of PTT is greatly restricted by the thermoresistance of tumor cells. Particularly, the compensatory expression of heat shock protein 90 (HSP90) has been found to significantly accelerate the thermal tolerance of tumor cells. Thus, a combination of HSP90 inhibitor and photothermal photosensitizer is expected to significantly enhance antitumor efficacy of PTT through hyperthermia sensitization. However, it remains challenging to precisely co-deliver two or more drugs into tumors. METHODS: A carrier-free co-delivery nanoassembly of gambogic acid (GA, a HSP90 inhibitor) and DiR is ingeniously fabricated based on a facile and precise molecular co-assembly technique. The assembly mechanisms, photothermal conversion efficiency, laser-triggered drug release, cellular uptake, synergistic cytotoxicity of the nanoassembly are investigated in vitro. Furthermore, the pharmacokinetics, biodistribution and self-enhanced PTT efficacy were explored in vivo. RESULTS: The nanoassembly presents multiple advantages throughout the whole drug delivery process, including carrier-free fabrication with good reproducibility, high drug co-loading efficiency with convenient dose adjustment, synchronous co-delivery of DiR and GA with long systemic circulation, as well as self-tracing tumor accumulation with efficient photothermal conversion. As expected, HSP90 inhibition-augmented PTT is observed in a 4T1 tumor BALB/c mice xenograft model. CONCLUSION: Our study provides a novel and facile dual-drug co-assembly strategy for self-sensitized cancer therapy.

The length of disulfide bond-containing linkages impacts the oral absorption and antitumor activity of paclitaxel prodrug-loaded nanoemulsions.

The rational design of oral paclitaxel (PTX) preparations is still a challenge. Many studies focus on developing PTX-loaded nanoemulsions (NEs) for oral administration. Unfortunately, PTX has poor affinity with the commonly used oil phases, leading to low encapsulation efficiency, poor colloidal stability, and premature drug leakage of PTX-loaded NEs. Herein, three lipophilic PTX prodrugs are synthesized by conjugating PTX with citronellol (CIT), using different lengths of disulfide bond-containing linkages. Interestingly, compared with PTX, the prodrugs exhibit higher affinity with the oil phase, effectively improving the encapsulation efficiency, colloidal stability, and sustained-release behavior of NEs. In addition, the disulfide bond-bridged prodrugs could specifically release PTX in tumor cells, reducing unnecessary systemic exposure of PTX. As a result, all three prodrug NEs exhibited improved oral bioavailability and antitumor effects compared to oral Taxol. Moreover, the length of disulfide bond-containing linkages exhibits great impacts on the oral absorption, drug release, and antitumor behaviors of NEs. It is found that the prodrug NEs with the shortest linkages show comparable antitumor effects with intravenous Taxol, but with less systemic and gastrointestinal toxicity.

Photosensitizer-driven nanoassemblies of homodimeric prodrug for self-enhancing activation and synergistic chemo-photodynamic therapy.

Carrier-free prodrug-nanoassemblies have emerged as promising nanomedicines. In particular, the self-assembled nanoparticles (NPs) composed of homodimeric prodrugs with ultrahigh drug loading have attracted broad attention. However, most homodimeric prodrugs show poor self-assembly ability due to their symmetric structures. Herein, we developed photosensitizer-driven nanoassemblies of homodimeric prodrug for self-enhancing activation and chemo-photodynamic synergistic therapy. Methods: In this work, a pyropheophorbide a (PPa)-driven nanoassemblies of an oxidation-responsive cabazitaxel homodimer (CTX-S-CTX) was fabricated (pCTX-S-CTX/PPa NPs). The assembly mechanisms, aggregation-caused quenching (ACQ) effect alleviation, singlet oxygen generation, self-enhancing prodrug activation, cellular uptake, intracellular reactive oxygen species (ROS) generation and synergistic cytotoxicity of pCTX-S-CTX/PPa NPs were investigated in vitro. Moreover, the pharmacokinetics, ex vivo biodistribution and in vivo therapeutic efficacy of pCTX-S-CTX/PPa NPs were studied in mice bearing 4T1 tumor. Results: Interestingly, PPa was found to drive the assembly of CTX-S-CTX, which cannot self-assemble into stable NPs alone. Multiple intermolecular forces were found to be involved in the assembly process. Notably, the nanostructure was destroyed in the presence of endogenous ROS, significantly relieving the ACQ effect of PPa. In turn, ROS generated by PPa under laser irradiation together with the endogenous ROS synergistically promoted prodrug activation. As expected, the nanoassemblies demonstrated potent antitumor activity in a 4T1 breast cancer BALB/c mice xenograft model. Conclusion: Our findings offer a simple strategy to facilitate the assembly of homodimeric prodrugs and provide an efficient nanoplatform for chemo-photodynamic therapy.

Erythrocyte membrane-camouflaged carrier-free nanoassembly of FRET photosensitizer pairs with high therapeutic efficiency and high security for programmed cancer synergistic phototherapy.

Phototherapy has been intensively investigated as a non-invasive cancer treatment option. However, its clinical translation is still impeded by unsatisfactory therapeutic efficacy and severe phototoxicity. To achieve high therapeutic efficiency and high security, a nanoassembly of Forster Resonance Energy Transfer (FRET) photosensitizer pairs is developed on basis of dual-mode photosensitizer co-loading and photocaging strategy. For proof-of-concept, an erythrocyte-camouflaged FRET pair co-assembly of chlorine e6 (Ce6, FRET donor) and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR, FRET acceptor) is investigated for breast cancer treatment. Notably, Ce6 in the nanoassemby is quenched by DiR and could be unlocked for photodynamic therapy (PDT) only when DiR is photobleached by 808-nm laser. As a result, Ce6-caused phototoxicity could be well controlled. Under cascaded laser irradiation (808-660 nm), tumor-localizing temperature rise following laser irradiation on DiR not only induces tumor cell apoptosis but also facilitates the tumor penetration of NPs, relieves tumor hypoxia, and promotes the PDT efficacy of Ce6. Such FRET pair-based nanoassembly provides a new strategy for developing multimodal phototherapy nanomedicines with high efficiency and good security.

Oxidation-strengthened disulfide-bridged prodrug nanoplatforms with cascade facilitated drug release for synergetic photochemotherapy.

One of the major barriers in utilizing prodrug nanocarriers for cancer therapy is the slow release of parent drug in tumors. Tumor cells generally display the higher oxidative level than normal cells, and also displayed the heterogeneity in terms of redox homeostasis level. We previously found that the disulfide bond-linkage demonstrates surprising oxidation-sensitivity to form the hydrophilic sulfoxide and sulphone groups. Herein, we develop oxidation-strengthened prodrug nanosystem loaded with pyropheophorbide a (PPa) to achieve light-activatable cascade drug release and enhance therapeutic efficacy. The disulfide bond-driven prodrug nanosystems not only respond to the redox-heterogeneity in tumor, but also respond to the exogenous oxidant (singlet oxygen) elicited by photosensitizers. Once the prodrug nanoparticles (NPs) are activated under irradiation, they would undergo an oxidative self-strengthened process, resulting in a facilitated drug cascade release. The IC50 value of the PPa@PTX-S-S NPs without irradiation was 2-fold higher than those of NPs plus irradiation. In vivo, the PPa@PTX prodrug NPs display prolonged systemic circulation and increased accumulation in tumor site. The PPa@PTX-S-S NPs showed much higher efficiency than free PTX or the PPa@PTX-C-C NPs to suppress the growth of 4T1 tumors. Therefore, this novel oxidation-strengthened disulfide-bridged prodrug-nanosystem has a great potential in the enhanced efficacy of cancer synergetic photochemotherapy.