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Eosinophils are important immune effector cells that affect T cell-mediated antitumor immunity. However, the low frequency and restrained activity of eosinophils restricted the outcome of cancer immunotherapies. We herein report an eosinophil-activating semiconducting polymer nanoparticle (SPNe) to improve photodynamic tumor immunogenicity, modulate eosinophil chemotaxis, and reinvigorate T-cell immunity for activated cancer photo-immunotherapy. SPNe comprises an amphiphilic semiconducting polymer and a dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin via a 1 O 2 -cleavable thioketal linker. Upon localized NIR photoirradiation, SPNe generates 1 O 2 to elicit immunogenic cell death of tumors and induce specific activation of sitagliptin. The subsequent inhibition of DPP4 increases intratumoral CCL11 levels to promote eosinophil chemotaxis and activation. SPNe-mediated photo-immunotherapy synergized with immune checkpoint blockade greatly promotes tumor infiltration and activation of both eosinophils and T cells, effectively inhibiting tumor growth and metastasis. Thus, this study presents a generic polymeric nanoplatform to modulate specific immune cells for precision cancer immunotherapy., (© 2024 Wiley-VCH GmbH.)

Combination photoimmunotherapy holds promise for tumor suppression; however, smart phototherapeutic agents that only activate their immune pharmaceutical action in tumors have been rarely developed. Herein, we report a semiconducting polymer (SP) nano-regulator (SPN T ) with cascading activation for combinational photodynamic cancer immunotherapy. SPN T comprises an immunoregulator (M-Trp: 1-methyltryptophan) conjugating to the side chain of the SP backbone via an apoptotic biomarker-cleavable linker. Under near-infrared photoirradiation, SPN T produces singlet oxygen to induce immunogenic apoptosis. Concurrently, an apoptotic biomarker is upregulated, which triggers the specific cleavage of M-Trp for indoleamine 2,3-dioxygenase (IDO) activity inhibition, regulatory T cells reduction and cytotoxic T lymphocytes infiltration. SPN T -mediated combination photodynamic immunotherapy thus reprograms the tumor immune microenvironment, resulting in efficient suppression of tumors, and inhibition of lung metastasis., (© 2021 Wiley-VCH GmbH.)

Nanomedicine can regulate the balance between cytotoxic T lymphocytes (CTLs) and suppressive regulatory T lymphocytes (Tregs), which however has been rarely exploited for cancer immunotherapy. We report a charge-reversal polymer nano-modulator (SP DMC N) activated by tumor microenvironment (TME) for photodynamic immunotherapy of cancer. SP DMC N is constructed by conjugating an immunomodulator (demethylcantharidin, DMC) to the side chains of a photodynamic polymer via an acid-liable linker. The negative charge of SP DMC N ensures its high stability in blood circulation and ideal tumor accumulation; exposure to acidic TME reverses its surface charge to positive, enhancing tumor penetration and locally releasing DMC. Upon near-infrared photoirradiation, SP DMC N generates singlet oxygen to ablate tumors and promote maturation of dendritic cells. Released DMC inhibits protein phosphatase 2 (PP2A) activity and decreases Tregs differentiation. Such combinational action induces a sharp increase in CTL/Treg ratio in TME and effectively inhibits both primary and distant tumors in living mice., (© 2021 Wiley-VCH GmbH.)

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 pro ) with phototherapeutic and activatable protein degradation abilities for photo-immunometabolic cancer therapy. SPN pro can remotely generate singlet oxygen ( 1 O 2 ) under NIR photoirradiation to eradicate tumor cells and induce immunogenic cell death (ICD) to enhance tumor immunogenicity. Moreover, the PROTAC function of SPN pro 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.

Development of real-time non-invasive imaging probes to assess infiltration and activation of cytotoxic T cells (CTLs) is critical to predict the efficacy of cancer immunotherapy, which however remains challenging. Reported here is an activatable semiconducting polymer nanoprobe (SPNP) for near-infrared fluorescence (NIRF) and photoacoustic (PA) imaging of a biomarker (granzyme B) associated with activation of CTLs. SPNP comprises a semiconducting polymer (SP) conjugated with a granzyme B cleavable and dye-labeled peptide as the side chain, both of which emit NIRF and PA signals. After systemic administration, SPNP passively targets the tumor and in situ reacts with granzyme B to release the dye-labeled peptide, leading to decreased NIRF and PA signals from the dye but unchanged signals from the polymer. Such ratiometric NIRF and PA signals of SPNP correlate well with the expression level of granzyme B and intratumoral population of CTLs. Thus, this study not only presents the first PA probes for in vivo imaging of immune activation but also provides a molecular design strategy that can be generalized for molecular imaging of other immune-related biomarkers., (© 2020 Wiley-VCH GmbH.)

Immunotherapy has offered new treatment options for cancer; however, the therapeutic benefits are often modest and desired to be improved. A semiconducting polymer nanoadjuvant (SPN II R) with a photothermally triggered cargo release for second near-infrared (NIR-II) photothermal immunotherapy is reported here. SPN II R consists of a semiconducting polymer nanoparticle core as an NIR-II photothermal converter, which is doped with a toll-like receptor (TLR) agonist as an immunotherapy adjuvant and coated with a thermally responsive lipid shell. Upon NIR-II photoirradiation, SPN II R effectively generates heat not only to ablate tumors and induce immunogenic cell death (ICD), but also to melt the lipid layers for on-demand release of the TLR agonist. The combination of ICD and activation of TLR7/TLR8 enhances the maturation of dendritic cells, which amplifies anti-tumor immune responses. Thus, a single treatment of SPN II R-mediated NIR-II photothermal immunotherapy effectively inhibits growth of both primary and distant tumors and eliminates lung metastasis in a murine mouse model. This study thus provides a remote-controlled smart delivery system to synergize photomedicine with immunotherapy for enhanced cancer treatment., (© 2020 Wiley-VCH GmbH.)

Discriminative detection of invasive and noninvasive breast cancers is crucial for their effective treatment and prognosis. However, activatable probes able to do so in vivo are rare. Herein, we report an activatable polymeric reporter (P-Dex) that specifically turns on near-infrared (NIR) fluorescent and photoacoustic (PA) signals in response to the urokinase-type plasminogen activator (uPA) overexpressed in invasive breast cancer. P-Dex has a renal-clearable dextran backbone that is linked with a NIR dye caged with an uPA-cleavable peptide substrate. Such a molecular design allows P-Dex to passively target tumors, activate NIR fluorescence and PA signals to effectively distinguish invasive MDA-MB-231 breast cancer from noninvasive MCF-7 breast cancer, and ultimately undergo renal clearance to minimize the toxicity potential. Thus, this polymeric reporter holds great promise for the early detection of malignant breast cancer., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Noninvasive regulation of CRISPR/Cas9 gene editing is conducive to understanding of gene function and development of gene therapy; however, it remains challenging. Herein, a photolabile semiconducting polymer nanotransducer (pSPN) is synthesized to act as the gene vector to deliver CRISPR/Cas9 plasmids into cells and also as the photoregulator to remotely activate gene editing. pSPN comprises a 1 O 2 -generating backbone grafted with polyethylenimine brushes through 1 O 2 -cleavable linkers. NIR photoirradiation spontaneously triggers the cleavage of gene vectors from pSPN, resulting in the release of CRISPR/Cas9 plasmids and subsequently initiating gene editing. This system affords 15- and 1.8-fold enhancement in repaired gene expression relative to the nonirradiated controls in living cells and mice, respectively. As this approach does not require any specific modifications on biomolecular components, pSPN represents the first generic nanotransducer for in vivo regulation of CRISPR/Cas9 gene editing., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

For the sake of protein stability and targeted application as blood substitutes, formulation customization of hemoglobin-loaded polymeric particles (HbP) was conducted via a double emulsion method. Screening of the emulsification parameters was firstly performed for the stability of Hb, and the structure and functions of recovered Hb could be well preserved via CD and UV-vis spectroscopy investigation. In the optimized conditions, Hb was loaded into the polymeric matrix formed of three material compositions. They were poly(ϵ-caprolactone)(PCL), poly(ethylene glycol)-block-poly(allyl glycidyl ether) (functionalized with mercaptopropionic acid)-block-poly(ϵ-caprolactone) (PEG-PAGE(MPA)-PCL), and the blend of the two polymers. The morphology, internal structure, in vitro leakage and hemocompatibility of the HbP products were characterized in detail, and the encapsulation mechanism was explored by the combined analysis of the encapsulation efficiency, non-specific protein adsorption and in vitro leakage studies. Results showed that the burst release effect found in homopolymers could be alleviated by use of block copolymers due to the reduced protein adsorption, and completely avoided by further cross-linking of particles through carbonyl-amino condensation reactions. The amphiphilic copolymers showed relatively high stability in blood and no interference with blood components compared with hydrophobic PCL. These results suggest that both the optimization of emulsion formation and material composition are prerequisite for stable formulations of Hb encapsulated in polymeric particles., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Eosinophils are important immune effector cells that affect T cell‐mediated antitumor immunity. However, the low frequency and restrained activity of eosinophils restricted the outcome of cancer immunotherapies. We herein report an eosinophil‐activating semiconducting polymer nanoparticle (SPNe) to improve photodynamic tumor immunogenicity, modulate eosinophil chemotaxis, and reinvigorate T‐cell immunity for activated cancer photo‐immunotherapy. SPNe comprises an amphiphilic semiconducting polymer and a dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin via a 1O2‐cleavable thioketal linker. Upon localized NIR photoirradiation, SPNe generates 1O2 to elicit immunogenic cell death of tumors and induce specific activation of sitagliptin. The subsequent inhibition of DPP4 increases intratumoral CCL11 levels to promote eosinophil chemotaxis and activation. SPNe‐mediated photo‐immunotherapy synergized with immune checkpoint blockade greatly promotes tumor infiltration and activation of both eosinophils and T cells, effectively inhibiting tumor growth and metastasis. Thus, this study presents a generic polymeric nanoplatform to modulate specific immune cells for precision cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Stimulus‐responsive large‐scale cell culture microcarriers are promising biological materials for large‐scale cell production. Herein, multifunctional thermal and magnetic microcarriers (TMMs) made of poly(N‐isopropylacrylamide) (PNIPAM), polylysines (PLLs), gelatin methacryloyl (GelMA), poly(ethylene glycol) diacrylate (PEGDA), N,N‐methylenebis(acrylamide) (MBA), Fe3O4 and SiO2 are prepared to achieve large‐scale enzyme‐free cell harvesting and also can be used as cells stereogrowth scaffold to mimic cells suspension state to develop novel application, such as recombinant proteins produced. In TMMs, NIPAM and other materials are mixed and then underwent in situ radical polymerization by UV irradition with 2‐hydroxy‐2‐methylpropiophenone as initiator, in which GelMA provides cell adhesion sites and PLLs enable a positive microenvironment with SiO2 as filler. As enzyme‐free cell microcarriers, cell harvesting from TMMs by PNIPAM are achieved at 25 °C through vortex oscillation within 15 min and TMMs can be recycled at least for four times by magnetic recovery. Moreover, TMMs can be used as stereoculture scaffold to let cells in suspension as adherent state to improve gene transfection efficiency. Combined with magnetothermal effect, TMMs can further improve gene transfer to obtain industrialization of proteins expression. Therefore, TMMs are potential for the development of cell manufacturing and the expansion of cell stereogrowth application for recombinant proteins production. [ABSTRACT FROM AUTHOR]

Combination photoimmunotherapy holds promise for tumor suppression; however, smart phototherapeutic agents that only activate their immune pharmaceutical action in tumors have been rarely developed. Herein, we report a semiconducting polymer (SP) nano‐regulator (SPNT) with cascading activation for combinational photodynamic cancer immunotherapy. SPNT comprises an immunoregulator (M‐Trp: 1‐methyltryptophan) conjugating to the side chain of the SP backbone via an apoptotic biomarker‐cleavable linker. Under near‐infrared photoirradiation, SPNT produces singlet oxygen to induce immunogenic apoptosis. Concurrently, an apoptotic biomarker is upregulated, which triggers the specific cleavage of M‐Trp for indoleamine 2,3‐dioxygenase (IDO) activity inhibition, regulatory T cells reduction and cytotoxic T lymphocytes infiltration. SPNT‐mediated combination photodynamic immunotherapy thus reprograms the tumor immune microenvironment, resulting in efficient suppression of tumors, and inhibition of lung metastasis. [ABSTRACT FROM AUTHOR]

Development of real‐time non‐invasive imaging probes to assess infiltration and activation of cytotoxic T cells (CTLs) is critical to predict the efficacy of cancer immunotherapy, which however remains challenging. Reported here is an activatable semiconducting polymer nanoprobe (SPNP) for near‐infrared fluorescence (NIRF) and photoacoustic (PA) imaging of a biomarker (granzyme B) associated with activation of CTLs. SPNP comprises a semiconducting polymer (SP) conjugated with a granzyme B cleavable and dye‐labeled peptide as the side chain, both of which emit NIRF and PA signals. After systemic administration, SPNP passively targets the tumor and in situ reacts with granzyme B to release the dye‐labeled peptide, leading to decreased NIRF and PA signals from the dye but unchanged signals from the polymer. Such ratiometric NIRF and PA signals of SPNP correlate well with the expression level of granzyme B and intratumoral population of CTLs. Thus, this study not only presents the first PA probes for in vivo imaging of immune activation but also provides a molecular design strategy that can be generalized for molecular imaging of other immune‐related biomarkers. [ABSTRACT FROM AUTHOR]

Discriminative detection of invasive and noninvasive breast cancers is crucial for their effective treatment and prognosis. However, activatable probes able to do so in vivo are rare. Herein, we report an activatable polymeric reporter (P‐Dex) that specifically turns on near‐infrared (NIR) fluorescent and photoacoustic (PA) signals in response to the urokinase‐type plasminogen activator (uPA) overexpressed in invasive breast cancer. P‐Dex has a renal‐clearable dextran backbone that is linked with a NIR dye caged with an uPA‐cleavable peptide substrate. Such a molecular design allows P‐Dex to passively target tumors, activate NIR fluorescence and PA signals to effectively distinguish invasive MDA‐MB‐231 breast cancer from noninvasive MCF‐7 breast cancer, and ultimately undergo renal clearance to minimize the toxicity potential. Thus, this polymeric reporter holds great promise for the early detection of malignant breast cancer. [ABSTRACT FROM AUTHOR]

Noninvasive regulation of CRISPR/Cas9 gene editing is conducive to understanding of gene function and development of gene therapy; however, it remains challenging. Herein, a photolabile semiconducting polymer nanotransducer (pSPN) is synthesized to act as the gene vector to deliver CRISPR/Cas9 plasmids into cells and also as the photoregulator to remotely activate gene editing. pSPN comprises a 1O2‐generating backbone grafted with polyethylenimine brushes through 1O2‐cleavable linkers. NIR photoirradiation spontaneously triggers the cleavage of gene vectors from pSPN, resulting in the release of CRISPR/Cas9 plasmids and subsequently initiating gene editing. This system affords 15‐ and 1.8‐fold enhancement in repaired gene expression relative to the nonirradiated controls in living cells and mice, respectively. As this approach does not require any specific modifications on biomolecular components, pSPN represents the first generic nanotransducer for in vivo regulation of CRISPR/Cas9 gene editing. [ABSTRACT FROM AUTHOR]

Keywords: activatable probe; cancer; near-infrared fluorescent probes; polymers; photoacoustic imaging EN activatable probe cancer near-infrared fluorescent probes polymers photoacoustic imaging 7005 7005 1 04/22/20 20200427 NES 200427 B Ein aktivierbarer polymerer Reporter b (P-Dex), der durch Nahinfrarot-Fluoreszenz und photoakustische Signale auf einen Biomarker (uPA) anspricht, wurde gezielt entworfen. GLO:OL3/27apr20:ange202003878-gra-0001.jpg PHOTO (COLOR): . gl B Nanographen b E. Maçôas, A. G. Campaña et al. zeigen in ihrem Forschungsartikel auf S. 7205, wie die Einführung eines Troponrings in ein Nanographenband die Upconversion-Emission verstärkt. Activatable probe, cancer, near-infrared fluorescent probes, polymers, photoacoustic imaging. [Extracted from the article]