This study reports the development of iron‐chelated semiconducting polycomplex nanoparticles (SPFeN) for photoacoustic (PA) imaging‐guided photothermal ferrotherapy of cancer. The hybrid polymeric ...nanoagent comprises a ferroptosis initiator (Fe3+) and an amphiphilic semiconducting polycomplex (SPC) serving as both the photothermal nanotransducer and iron ion chelator. By virtue of poly(ethylene glycol) (PEG) grafting and its small size, SPFeN accumulates in the tumor of living mice after systemic administration, which can be monitored by PA imaging. In the acidic tumor microenvironment, SPFeN generates hydroxyl radicals, leading to ferroptosis; meanwhile, under NIR laser irradiation, it generates localized heat to not only accelerate the Fenton reaction but also implement photothermal therapy. Such a combined photothermal ferrotherapeutic effect of SPFeN leads to minimized dosage of iron compared to previous studies and effectively inhibits the tumor growth in living mice, which is not possible for the controls.
Iron‐chelated semiconducting polycomplex nanoparticles (SPFeN) with theability to induce ferroptosis and a near‐infrared photothermal effect were developed for photoacoustic imaging‐guided combination cancer therapy.
Immunometabolic intervention has been applied to treat cancer via inhibition of certain enzymes associated with intratumoral metabolism. However, small-molecule inhibitors and genetic modification ...often suffer from insufficiency and off-target side effects. Proteolysis targeting chimeras (PROTACs) provide an alternative way to modulate protein homeostasis for cancer therapy; however, the always-on bioactivity of existing PROTACs potentially leads to uncontrollable protein degradation at non-target sites, limiting their in vivo therapeutic efficacy. We herein report a semiconducting polymer nano-PROTAC (SPN
) with phototherapeutic and activatable protein degradation abilities for photo-immunometabolic cancer therapy. SPN
can remotely generate singlet oxygen (
O
) under NIR photoirradiation to eradicate tumor cells and induce immunogenic cell death (ICD) to enhance tumor immunogenicity. Moreover, the PROTAC function of SPN
is specifically activated by a cancer biomarker (cathepsin B) to trigger targeted proteolysis of immunosuppressive indoleamine 2,3-dioxygenase (IDO) in the tumor of living mice. The persistent IDO degradation blocks tryptophan (Trp)-catabolism program and promotes the activation of effector T cells. Such a SPNpro-mediated in-situ immunometabolic intervention synergizes immunogenic phototherapy to boost the antitumor T-cell immunity, effectively inhibiting tumor growth and metastasis. Thus, this study provides a polymer platform to advance PROTAC in cancer therapy.
Cancer theranostics holds potential promise for precision medicine; however, most existing theranostic nanoagents are simply developed by doping both therapeutic agents and imaging agent into one ...particle entity, and thus have an “always‐on” pharmaceutical effect and imaging signals regardless of their in vivo location. Herein, the development of an organic afterglow protheranostic nanoassembly (APtN) that specifically activates both the pharmaceutical effect and diagnostic signals in response to a tumor‐associated chemical mediator (hydrogen peroxide, H2O2) is reported. APtN comprises an amphiphilic macromolecule and a near‐infrared (NIR) dye acting as the H2O2‐responsive afterglow prodrug and the afterglow initiator, respectively. Such a molecular architecture allows APtN to passively target tumors in living mice, specifically release the anticancer drug in the tumor, and spontaneously generate the uncaged afterglow substrate. Upon NIR light preirradiation, the afterglow initiator generates singlet oxygen to react and subsequently transform the uncaged afterglow substrate into an active self‐luminescent form. Thus, the intensity of generated afterglow luminescence is correlated with the drug release status, permitting real‐time in vivo monitoring of prodrug activation. This study proposes a background‐free design strategy toward activatable cancer theranostics.
An organic afterglow protheranostic nanoassembly is developed to specifically activate both pharmaceutical drug and diagnostic afterglow signals in the tumor microenvironment by a tumor‐associated chemical mediator (H2O2) for cancer theranostics.
Protease inhibitors can modulate intratumoral metabolic processes to reprogram the immunosuppressive tumor microenvironment (TME), which however suffer from the limited efficacy and off‐targeted side ...effects. We report smart nano‐proteolysis targeting chimeras (nano‐PROTACs) with phototherapeutic ablation and cancer‐specific protein degradation to reprogram the TME for photo‐metabolic cancer immunotherapy. This nano‐PROTAC has a semiconducting polymer backbone linked with a cyclooxygenase 1/2 (COX‐1/2)‐targeting PROTAC peptide (CPP) via a cathepsin B (CatB)‐cleavable segment. CPP can be activated by the tumor‐overexpressed CatB to induce the degradation of COX‐1/2 via the ubiquitin‐proteasome system. The persistent degradation of COX‐1/2 depletes their metabolite prostaglandin E2 which is responsible for activation of immune suppressor cells. Such a smart PROTAC strategy synergized with phototherapy specifically reprograms the immunosuppressive TME and reinvigorates antitumor immunity.
The smart nano‐proteolysis targeting chimeras (nano‐PROTACs) are developed for photo‐metabolic cancer immunotherapy. SPNCOX‐mediated therapy can not only improve tumor immunogenicity but also induce targeted intratumoral degradation of COX‐1/2 via the ubiquitin‐proteasome system, leading to the depletion of prostaglandin E2 (PGE2) and reprogramming of the immunosuppressive TME to inhibit tumor growth, metastasis, and recurrence.
Optical nanoparticles are promising diagnostic tools; however, their shallow optical imaging depth and slow clearance from the body have impeded their use for in vivo disease detection. To address ...these limitations, we develop activatable polyfluorophore nanosensors with biomarker-triggered nanoparticle-to-molecule pharmacokinetic conversion and near-infrared fluorogenic turn-on response. Activatable polyfluorophore nanosensors can accumulate at the disease site and react with disease-associated proteases to undergo in situ enzyme-catalysed depolymerization. This disease-specific interaction liberates renal-clearable fluorogenic fragments from activatable polyfluorophore nanosensors for non-invasive longitudinal urinalysis and outperforms the gold standard blood and urine assays, providing a level of sensitivity and specificity comparable to those of invasive biopsy and flow cytometry analysis. In rodent models, activatable polyfluorophore nanosensors enable ultrasensitive detection of tumours (1.6 mm diameter) and early diagnosis of acute liver allograft rejection. We anticipate that our modular nanosensor platform may be applied for early diagnosis of a range of diseases via a simple urine test.
In this study, an organic semiconducting pro‐nanostimulant (OSPS) with a near‐infrared (NIR) photoactivatable immunotherapeutic action for synergetic cancer therapy is presented. OSPS comprises a ...semiconducting polymer nanoparticle (SPN) core and an immunostimulant conjugated through a singlet oxygen (1O2) cleavable linkers. Upon NIR laser irradiation, OSPS generates both heat and 1O2 to exert combinational phototherapy not only to ablate tumors but also to produce tumor‐associated antigens. More importantly, NIR irradiation triggers the cleavage of 1O2‐cleavable linkers, triggering the remote release of the immunostimulants from OSPS to modulate the immunosuppressive tumor microenvironment. Thus, the released tumor‐associated antigens in conjunction with activated immunostimulants induce a synergistic antitumor immune response after OSPS‐mediated phototherapy, resulting in the inhibited growth of both primary/distant tumors and lung metastasis in a mouse xenograft model, which is not observed for sole phototherapy.
An organic semiconducting pro‐nanostimulant was developed for synergetic cancer therapy. Only upon near‐infrared (NIR) irradiation is the pro‐nanostimulant activated to simultaneously exert phototherapy and checkpoint blockade immunotherapy, inhibiting the growth of primary/distant tumors and significantly suppressing the lung metastasis without causing any obvious in vivo toxicity.
The limitation for the biomedical application of porous organic polymers (POPs) is the big size and poor dispersibility in aqueous media. Herein, a nanoscale metal–organic framework (MOF)@POP ...composite, named UNM, has been synthesized by epitaxial growth of the photoactive porphyrin-POPs (H2P-POP) on the outer surface of amine containing UiO-66 (UiO-AM). After the growth of POPs, the crystallization, pore structure, and size distribution of UNM are retained well. The formed UNM possesses a small size of less than 200 nm and could be internalized by cancer cells. Such light-activated UNM exhibits efficient ability to generate 1O2 under various experimental conditions, which can be further applied for PDT efficacy. The present work demonstrates the great potential of nanoscale porous polymers in biomedical fields and cancer treatment.
Combination of chemotherapy and gene therapy provides an effective strategy for cancer treatment. However, the lack of suitable codelivery systems with efficient endo/lysosomal escape and ...controllable drug release/gene unpacking is the major bottleneck for maximizing the combinational therapeutic efficacy. In this work, we developed a photoactivatable Pt(IV) prodrug-backboned polymeric nanoparticle system (CNPPtCP/si(c‑fos)) for light-controlled si(c-fos) delivery and synergistic photoactivated chemotherapy (PACT) and RNA interference (RNAi) on platinum-resistant ovarian cancer (PROC). Upon blue-light irradiation (430 nm), CNPPtCP/si(c‑fos) generates oxygen-independent N3 • with mild oxidation energy for efficient endo/lysosomal escape through N3 •-assisted photochemical internalization with less gene deactivation. Thereafter, along with Pt(IV) prodrug activation, CNPPtCP/si(c‑fos) dissociates to release active Pt(II) and unpack si(c-fos) simultaneously. Both in vitro and in vivo results demonstrated that CNPPtCP/si(c‑fos) displayed excellent synergistic therapeutic efficacy on PROC with low toxicity. This PACT prodrug-backboned polymeric nanoplatform may provide a promising gene/drug codelivery tactic for treatment of various hard-to-tackle cancers.
Cultivated strawberry, one of the major fruit crops worldwide, is an evergreen plant with shallow root system, and thus sensitive to environmental changes, including drought stress. To investigate ...the effect of 5‐aminolevulinic acid (ALA), a new environment‐friendly plant growth regulator, on strawberry drought tolerance and its possible mechanisms, we treated strawberry (Fragaria × annanasa Duch. cv. ‘Benihoppe’) with 15% polyethylene glycol 6000 to simulate osmotic stress with or without 10 mg l−1 ALA. We found that ALA significantly alleviated PEG‐inhibited plant growth and improved water absorption and xylem sap flux, indicating ALA mitigates the adverse effect of osmotic stress on strawberry plants. Gas exchange and chlorophyll fluorescence analysis showed that ALA mitigated PEG‐induced decreases of Pn, Gs, Tr, Pn/Ci, photosystem I and II reaction center activities, electron transport activity, and photosynthetic performance indexes. Equally important, ALA promoted PEG‐increased antioxidant enzyme activities and repressed PEG‐increased malondialdehyde and superoxide anion in both leaves and roots. Specially, ALA repressed H2O2 increase in leaves, but stimulated it in roots. Furthermore, ALA repressed abscisic acid (ABA) biosynthesis and signaling gene expressions in leaves, but promoted those in roots. In addition, ALA blocked PEG‐downregulated expressions of plasmalemma and tonoplast aquaporin genes PIP and TIP in both leaves and roots. Taken together, ALA effectively enhances strawberry drought tolerance and the mechanism is related to the improvement of water absorption and conductivity. The tissue‐specific responses of ABA biosynthesis, ABA signaling, and H2O2 accumulation to ALA in leaves and roots play key roles in ALA‐improved strawberry tolerance to osmotic stress.
Osteosarcoma is the most common primary bone malignancy in children and adolescents. Although improvements in therapeutic strategies were achieved, the outcome remains poor for most patients with ...metastatic or recurrent osteosarcoma. Therefore, it is imperative to identify novel and effective prognostic biomarker and therapeutic targets for the disease. Long noncoding RNAs (lncRNAs) are a novel class of RNA molecules defined as transcripts >200 nucleotides that lack protein coding potential. Many lncRNAs are deregulated in cancer and are important regulators for malignancies. Nine lncRNAs (91H, BCAR4, FGFR3-AS1, HIF2PUT, HOTTIP, HULC, MALAT-1, TUG1, UCA1) are upregulated and considered oncogenic for osteosarcoma. Loc285194 and MEG3 are two lncRNAs downregulated and as tumor suppressor for the disease. Moreover, the expressions of LINC00161 and ODRUL are associated with chemo-resistance of osteosarcoma. The mechanisms for these lncRNAs in regulating development of osteosarcoma are diverse, e.g. ceRNA, Wnt/β-catenin pathway, etc. The lncRNAs identified may serve as potential biomarkers or therapeutic targets for osteosarcoma.
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