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Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder leading to cognitive decline. Excessive cytosolic calcium (Ca2+) accumulation plays a critical role in the pathogenesis of AD since it activates the NOD-like receptor family, pyrin domain containing 3 (NLRP3), switches the endoplasmic reticulum (ER) unfolded protein response (UPR) toward proapoptotic signaling and promotes Aß seeding. Herein, a liposomal nanodrug (felodipine@LND) is developed incorporating a calcium channel antagonist felodipine for Alzheimer's disease treatment through a low-intensity pulse ultrasound (LIPUS) irradiation-assisted blood brain barrier (BBB)-crossing drug delivery. The multifunctional felodipine@LND is effectively delivered to diseased brain through applying a LIPUS irradiation to the skull, which resulted in a series of positive effects against AD. Markedly, the nanodrug treatment switched the ER UPR toward antioxidant signaling, prevented the surface translocation of ER calreticulin (CALR) in microglia, and inhibited the NLRP3 activation and Aß seeding. In addition, it promoted the degradation of damaged mitochondria via mitophagy, thereby inhibiting the neuronal apoptosis. Therefore, the anxiety-like behavior and cognitive impairment of 5xFAD mice with AD is significantly ameliorated, which manifested the potential of LIPUS - assisted BBB-crossing delivery of felodipine@LND to serve as a paradigm for AD therapy based on the well-recognized clinically available felodipine.
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The applications of hydrogels have expanded significantly due to their versatile, highly tunable properties and breakthroughs in biomaterial technologies. In this review, we cover the major achievements and the potential of hydrogels in therapeutic applications, focusing primarily on two areas: emerging cell-based therapies and promising non-cell therapeutic modalities. Within the context of cell therapy, we discuss the capacity of hydrogels to overcome the existing translational challenges faced by mainstream cell therapy paradigms, provide a detailed discussion on the advantages and principal design considerations of hydrogels for boosting the efficacy of cell therapy, as well as list specific examples of their applications in different disease scenarios. We then explore the potential of hydrogels in drug delivery, physical intervention therapies, and other non-cell therapeutic areas (e.g., bioadhesives, artificial tissues, and biosensors), emphasizing their utility beyond mere delivery vehicles. Additionally, we complement our discussion on the latest progress and challenges in the clinical application of hydrogels and outline future research directions, particularly in terms of integration with advanced biomanufacturing technologies. This review aims to present a comprehensive view and critical insights into the design and selection of hydrogels for both cell therapy and non-cell therapies, tailored to meet the therapeutic requirements of diverse diseases and situations.
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Terapia Baseada em Transplante de Células e Tecidos , Sistemas de Liberação de Medicamentos , Hidrogéis , Hidrogéis/química , Hidrogéis/uso terapêutico , Humanos , Terapia Baseada em Transplante de Células e Tecidos/tendências , Materiais Biocompatíveis/uso terapêutico , Materiais Biocompatíveis/química , Animais , Engenharia Tecidual/tendênciasRESUMO
The development of manganese oxide-based chemodynamic immunotherapy is emerging as a key strategy against solid tumors. However, the limited efficacy of nanoplatform in inducing efficient tumor therapeutic effects and creating the prominent antitumor immune responses remains a crucial issue. In this study, we construct a novel multifunctional biomimetic nanovaccine comprising manganese oxide-loaded poly(2-diisopropylaminoethyl methacrylate) (MP) nanoparticles and a coating layer of hybrid cell membrane (RHM) derived from manganese oxide-remodeled 4T1 cells and dendritic cells (DCs) (collectively called MP@RHM) for combination chemodynamic immunotherapy. Compared with the nanovaccines coated with the single cell membrane, the MP@RHM nanovaccine highly efficiently activates both DCs and T cells to boost tumor-specific T cell, owing to the synergistic effects of abundant damage-associated molecular patterns, Mn2+, and T cell-stimulating moieties. Upon peritumoral injection, the MP@RHM nanovaccine targets both the tumor site for focused chemodynamic therapy and the lymph nodes for robust tumor-specific T cell priming, thereby achieving highly efficient chemodynamic immunotherapy. Moreover, as a preventive cancer nanovaccine, MP@RHM generates strong immunological memory to inhibit postoperative tumor metastasis and recurrence. Our study findings highlight a promising approach to construct a multifunctional biomimetic nanovaccine for personalized chemodynamic immunotherapy against solid tumors.
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Vacinas Anticâncer , Imunoterapia , Compostos de Manganês , Óxidos , Linfócitos T , Compostos de Manganês/química , Animais , Vacinas Anticâncer/imunologia , Óxidos/química , Linhagem Celular Tumoral , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Imunoterapia/métodos , Camundongos , Nanopartículas/química , Camundongos Endogâmicos BALB C , Feminino , Células Dendríticas/imunologia , Células Dendríticas/efeitos dos fármacos , Materiais Biomiméticos/química , Neoplasias/terapia , Neoplasias/imunologia , NanovacinasRESUMO
Triple negative breast cancer (TNBC) exhibits limited responsiveness to immunotherapy owing to its immunosuppressive tumor microenvironment (TME). Here, a reactive oxygen species (ROS)-labile nanodrug encapsulating the photosensitizer Ce6 and Bcl-2 inhibitor ABT-737 was developed to provoke a robust immune response via the synergistic effect of photodynamic therapy (PDT) and the reversal of apoptosis resistance. Upon exposure to first-wave near-infrared laser irradiation, the generated ROS triggers PEG cleavage, facilitating the accumulation of the nanodrug at tumor region and endocytosis by tumor cells. Further irradiation leads to the substantial generation of cytotoxic ROS, initiating an immunogenic cell death (ICD) cascade, which prompts the maturation of dendritic cells (DCs) as well as the infiltration of T cells into the tumor site. Meanwhile, Bcl-2 inhibition counteracts apoptosis resistance, thereby amplifying PDT-induced ICD and bolstering antitumor immunity. As a result, the ROS-sensitive nanodrug demonstrates a potent inhibitory effect on tumor growth.
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Apoptose , Compostos de Bifenilo , Imunoterapia , Fotoquimioterapia , Fármacos Fotossensibilizantes , Espécies Reativas de Oxigênio , Sulfonamidas , Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/terapia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/imunologia , Humanos , Apoptose/efeitos dos fármacos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/administração & dosagem , Feminino , Espécies Reativas de Oxigênio/metabolismo , Animais , Camundongos , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/química , Sulfonamidas/farmacologia , Sulfonamidas/química , Clorofilídeos , Linhagem Celular Tumoral , Piperazinas/farmacologia , Piperazinas/química , Nitrofenóis/farmacologia , Nitrofenóis/química , Nanopartículas/química , Porfirinas/farmacologia , Porfirinas/química , Antineoplásicos/farmacologia , Antineoplásicos/químicaRESUMO
Nowadays, effective immunotherapy against triple-negative breast cancer (TNBC) remains challenging due to the immunosuppressive tumor microenvironment. Immune checkpoint inhibitor is mostly employed to restore the activity of tumor-specific immune cells, which however brings little therapeutic outcome owing to the limited number of tumor-infiltrating CD8+ T cells and the inefficient delivery of immune drugs to the tumor tissue. Aiming to solve these problems, we herein constructed a tailor-made dissolving microneedle co-encapsulating the TLR7/8 agonist R848 and the immune checkpoint inhibitor aPD-1, termed αNP-RNP@DMN, and fabricated it as a transdermal drug delivery system. This well-designed microneedle patch, endowed with efficient tumor drug delivery ability, was able to mature tumor-infiltrating dendritic cells (TIDCs) and further promote the infiltration of CD8+ T cells into the tumor tissue with the aid of R848. Moreover, the introduction of aPD-1 blocked the programmed cell death protein 1/programmed cell death ligand 1(PD-1/PD-L1) immune checkpoints, synergistically reversing the immunosuppressive microenvironment of TNBC. In vivo therapeutic results demonstrated that αNP-RNP@DMN not only significantly prolonged the survival time of 4T1 tumor-bearing mice, but also inhibited tumor recurrence and lung metastasis after surgery, implying the great potential of this effective drug delivery system for enhanced immunotherapy of superficial tumors. STATEMENT OF SIGNIFICANCE: The limited number of tumor-infiltrating CD8+ T cells and the inefficient delivery of immune drugs to the tumor tissue hinder the effective immunotherapy of triple-negative breast cancer (TNBC). Herein, a dissolving microneedle co-encapsulating TLR7/8 agonist R848 and immune checkpoint inhibitor aPD-1 was developed and fabricated as a transdermal drug delivery system. This tailor-made microneedle patch not only promoted drug accumulation in tumor sites in a safe and painless manner, but also lifted the immune-suppressive state of tumor-infiltrating dendritic cells (TIDCs). The activated TIDCs further enhanced T-cell infiltration into the tumor tissue, thus successfully boosting the therapeutic efficacy of aPD-1. This study demonstrated that this well-designed microneedle patch could be served as an effective drug delivery system for enhanced immunotherapy of TNBC.
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Nanopartículas , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Neoplasias de Mama Triplo Negativas/patologia , Linfócitos T CD8-Positivos , Inibidores de Checkpoint Imunológico/uso terapêutico , Receptor 7 Toll-Like , Recidiva Local de Neoplasia/tratamento farmacológico , Imunoterapia/métodos , Microambiente TumoralRESUMO
Thermal ablation is a crucial therapeutic modality for hepatocellular carcinoma (HCC), but its efficacy is often hindered by the high recurrence rate attributed to insufficient ablation. Furthermore, the residual tumors following insufficient ablation exhibit a more pronounced immunosuppressive state, which accelerates the disease progression and leads to immune checkpoint blockade (ICB) resistance. Herein, evidence is presented that heightened intratumoral lactate accumulation, stemming from the augmented glycolytic activity of postablative residual HCC cells, may serve as a crucial driving force in exacerbating the immunosuppressive state of the tumor microenvironment (TME). To address this, an injectable nanoparticles-hydrogel composite system (LOX-MnO2 @Gel) is designed that gradually releases lactate oxidase (LOX)-loaded hollow mesoporous MnO2 nanoparticles at the tumor site to continuously deplete intratumoral lactate via a cascade catalytic reaction. Using subcutaneous and orthotopic HCC tumor-bearing mouse models, it is confirmed that LOX-MnO2 @Gel-mediated local lactate depletion can transform the immunosuppressive postablative TME into an immunocompetent one and synergizes with ICB therapy to significantly inhibit residual HCC growth and lung metastasis, thereby prolonging the survival of mice postablation. The work proposes an appealing strategy for synergistically combining antitumor metabolic therapy with immunotherapy to combat postablative HCC recurrence.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Animais , Camundongos , Ácido Láctico , Carcinoma Hepatocelular/terapia , Hidrogéis , Compostos de Manganês/farmacologia , Neoplasias Hepáticas/terapia , Óxidos , Imunoterapia , Microambiente TumoralRESUMO
The protective blood-brain barrier (BBB) prevents most therapeutic agents from entering the brain. Currently, focused ultrasound (FUS) is mostly employed to create microbubbles that induce a cavitation effect to open the BBB. However, microbubbles pass quickly through brain microvessels, substantially limiting the cavitation effect. Here, we constructed a novel perfluoropropane-loaded microbubble, termed ApoER-Pep-MB, which possessed a siloxane bonds-crosslinked surface to increase the microbubble stability against turbulence in blood circulation and was decorated with binding peptide for apolipoprotein E receptor (ApoER-Pep). The microbubble with tailor-made micron size (2 µm) and negative surface charge (-30 mV) performed ApoER-mediated binding rather than internalization into brain capillary endothelial cells. Consequently, the microbubble accumulated on the brain microvessels, based on which even a low-energy ultrasound with less safety risk than FUS, herein diagnostic ultrasound (DUS), could create a strong cavitation effect to open the BBB. Evans Blue and immunofluorescence staining studies demonstrated that the DUS-triggered cavitation effect not only temporarily opened the BBB for 2 h but also caused negligible damage to the brain tissue. Therefore, various agents, ranging from small molecules to nanoscale objects, can be efficiently delivered to target regions of the brain, offering tremendous opportunities for the treatment of brain diseases.
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Barreira Hematoencefálica , Microbolhas , Barreira Hematoencefálica/metabolismo , Células Endoteliais , Ultrassonografia , EndotélioRESUMO
The treatment of drug-resistant tumors poses a significant challenge in the field of tumor therapy. Disrupting the homeostasis of reactive oxygen species (ROS) within tumor cells may represent a pivotal strategy for overcoming the prevalent issue of drug resistance. However, the restricted sustainability of ROS generation and the increased autophagy capacity exhibited by tumor cells hinder the application of ROS-based therapies. In this study, we developed liposome nanoparticles (Ato/CQ@L) for co-encapsulation of atorvastatin (Ato), an activator of AMP-activated protein kinase (AMPK), and chloroquine (CQ), an autophagy inhibitor. Upon internalization by tumor cells, Ato upregulated carnitine palmitoyltransferase 1(CPT1) concentration and promoted fatty acid oxidation (FAO) within the tumor cells. The process of FAO coupled with an abundance of fatty acid substrates, facilitates a sustained generation of ROS production. Concurrently, a positive feedback loop is established between escalated concentration of ROS and AMPK protein levels, resulting in a persistent elevation in ROS levels. In addition, CQ disrupted lysosomes, leading to an increased lysosomal pH and reducing autophagy in tumor cells. In both in vivo and in vitro experiments, the Ato/CQ@L treatment group exhibited a considerable enhancement in tumor cell apoptosis, validating the efficacy of this combined therapy. In summary, the combined therapy involving Ato and CQ addresses the inherent limitations of conventional ROS therapy, which include insufficient ROS production and increased autophagy. This approach holds significant potential as a treatment strategy for drug-resistant triple-negative breast cancer.
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Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense extracellular matrix flooded with immune suppressive cells, resulting in extremely poor clinical response to immunotherapy. It has been revealed that the activation of pancreatic stellate cells (PSCs) makes considerable contributions to the immunological "cold" tumor microenvironment (TME). Herein, we developed a polyamino acid-based nanodrug incorporating the PSC activation inhibitor calcipotriol and anti-CXCL12 siRNA. The nanodrug was easily prepared with a small particle size and is capable of penetrating pancreatic tumors to inactivate PSCs and downregulate CXCL12. The in vivo results of orthotopic pancreatic tumor treatment demonstrated that codelivery of calcipotriol and anti-CXCL12 siRNA remodeled the PDAC TME with reduced extracellular matrix and decreased immunosuppressive T cells. Eventually, the infiltration of cytotoxic T cells was increased, thereby acting with immune checkpoint blockade (ICB) therapy for immunologically "cold" pancreatic tumors. In the present study, we propose a promising paradigm to improve the immunotherapy outcome of PDAC using nanodrugs that synchronously inhibit PSC activation and regulatory T-cell infiltration. STATEMENT OF SIGNIFICANCE: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense extracellular matrix (ECM) that impedes the tumor infiltration of therapeutic agents and cytotoxic T lymphocytes, resulting in a poor clinical response to immunotherapy. In the present study, we proposed a promising approach for enhanced immunotherapy of pancreatic cancer. Specifically, a nanodrug incorporating calcipotriol and anti-CXCL12 siRNA was synthesized to synchronously inactivate matrix-producing pancreatic stellate cells and suppress the infiltration of regulatory T cells. The reduced ECM removed the pathological barrier, preventing nanodrug penetration and effector T-cell infiltration, leading to a conversion of the immunosuppressive "cold" microenvironment to a "hot" microenvironment, which eventually boosted the immunotherapy of anti-PD-1 antibodies in pancreatic cancer.
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Carcinoma Ductal Pancreático , Nanopartículas , Neoplasias Pancreáticas , Humanos , Linfócitos T Reguladores/patologia , Células Estreladas do Pâncreas/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Imunoterapia , Nanopartículas/uso terapêutico , Microambiente Tumoral , Neoplasias PancreáticasRESUMO
Pyroptosis is a proinflammatory form of programmed cell death that results in the release of cellular contents and activation of immune responses. However, GSDME (a pyroptosis-executed protein) is suppressed in many cancers. Herein, we constructed a nanoliposome (GM@LR) for codelivering the GSDME-expressing plasmid and manganese carbonyl (MnCO) into TNBC cells. MnCO generated Mn2+ and carbon monoxide (CO) in the presence of H2O2. The CO-activated caspase-3, which cleaved the expressed GSDME, converting apoptosis to pyroptosis in 4T1 cells. In addition, Mn2+ promoted maturation of dendritic cells (DCs) by the activation of STING signaling pathway. The increased proportion of intratumoral mature DCs brought about massive infiltration of cytotoxic lymphocytes, leading to a robust immune response. Besides, Mn2+ could be applied for magnetic resonance imaging (MRI)-guided metastasis detection. Taken together, our study showed that GM@LR nanodrug could effectively inhibit tumor growth via pyroptosis and STING activation combined immunotherapy.
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Nanopartículas , Neoplasias de Mama Triplo Negativas , Linhagem Celular Tumoral , Peróxido de Hidrogênio/farmacologia , Nanopartículas/uso terapêutico , Nucleotidiltransferases/farmacologia , Piroptose , Feminino , Animais , CamundongosRESUMO
The dense extracellular matrix (ECM) is a key barrier to tumor infiltration of cytotoxic T lymphocytes (CTLs), which greatly compromises T cell-dependent immunotherapy of hepatocellular carcinoma (HCC). Herein, hyaluronidase (HAase), IL-12, and anti-PD-L1 antibody (αPD-L1) were co-delivered using a pH and MMP-2 dual-sensitive polymer/calcium phosphate (CaP) hybrid nanocarrier. The dissolution of CaP triggered by tumor acidity facilitated the release of IL-12 and HAase responsible for ECM digestion, enhancing the tumor infiltration and proliferation of CTLs. Furthermore, the in situ-released αPD-L1 inside tumor, as triggered by an overexpressed MMP-2, prevented the tumor cell from escaping the killing effects of CTLs. Such combination strategy induced a robust antitumor immunity for efficiently suppressing HCC growth in mice. Additionally, tumor acidity-sheddable polyethylene glycol (PEG) coating enhanced the tumor accumulation of nanocarrier and reduced the immune-related adverse events (irAEs) induced by on-target off-tumor αPD-L1. This dual-sensitive nanodrug demonstrates an effective immunotherapy paradigm for other dense ECM-characterized solid tumors.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Animais , Camundongos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Metaloproteinase 2 da Matriz , Neoplasias Hepáticas/patologia , Linhagem Celular Tumoral , Imunoterapia , Interleucina-12 , Nanopartículas/uso terapêutico , Microambiente TumoralRESUMO
BACKGROUND: Immune checkpoint blockade (ICB) monotherapy provides poor survival benefit in hepatocellular carcinoma (HCC) due to ICB resistance caused by immunosuppressive tumor microenvironment (TME) and drug discontinuation resulting from immune-related side effects. Thus, novel strategies that can simultaneously reshape immunosuppressive TME and ameliorate side effects are urgently needed. METHODS: Both in vitro and orthotopic HCC models were used to explore and demonstrate the new role of a conventional, clinically used drug, tadalafil (TA), in conquering immunosuppressive TME. In detail, the effect of TA on M2 polarization and polyamine metabolism in tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) was identified. After making clear the aforementioned immune regulatory effect of TA, we introduced a nanomedicine-based strategy of tumor-targeted drug delivery to make better use of TA to reverse immunosuppressive TME and overcome ICB resistance for HCC immunotherapy. A dual pH-sensitive nanodrug simultaneously carrying both TA and programmed cell death receptor 1 antibody (aPD-1) was developed, and its ability for tumor-targeted drug delivery and TME-responsive drug release was evaluated in an orthotopic HCC model. Finally, the immune regulatory effect, antitumor therapeutic effect, as well as side effects of our nanodrug combining both TA and aPD-1 were analyzed. RESULTS: TA exerted a new role in conquering immunosuppressive TME by inhibiting M2 polarization and polyamine metabolism in TAMs and MDSCs. A dual pH-sensitive nanodrug was successfully synthesized to simultaneously carry both TA and aPD-1. On one hand, the nanodrug realized tumor-targeted drug delivery by binding to circulating programmed cell death receptor 1-positive T cells and following their infiltration into tumor. On the other hand, the nanodrug facilitated efficient intratumoral drug release in acidic TME, releasing aPD-1 for ICB and leaving TA-encapsulated nanodrug to dually regulate TAMs and MDSCs. By virtue of the combined application of TA and aPD-1, as well as the efficient tumor-targeted drug delivery, our nanodrug effectively inhibited M2 polarization and polyamine metabolism in TAMs and MDSCs to conquer immunosuppressive TME, which contributed to remarkable ICB therapeutic efficacy with minimal side effects in HCC. CONCLUSIONS: Our novel tumor-targeted nanodrug expands the application of TA in tumor therapy and holds great potential to break the logjam of ICB-based HCC immunotherapy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Tadalafila/farmacologia , Tadalafila/uso terapêutico , Neoplasias Hepáticas/patologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos T , Terapia de Imunossupressão , Poliaminas/farmacologia , Poliaminas/uso terapêutico , Microambiente TumoralRESUMO
Triple negative breast cancer (TNBC) as a highly aggressive and metastatic malignancy lacks targeting therapies nowadays. Moreover, although immune checkpoint blockade (ICB) is known to trigger anti-tumor immune response, most TNBC falls into the immunologically "cold" category unsuitable for ICB therapy due to insufficient lymphocyte infiltration. Herein, we develop a hierarchical targeting strategy for preparing a core-shell-structural nanodrug to concurrently block the programmed death ligand 1 (PD-L1) and deliver a stimulator of interferon gene (STING) agonist into tumor-infiltrating antigen-presenting cells (APCs). The nanodrug complexed the interferon stimulatory DNA (ISD) for STING activation in its core, conjugated PD-L1 antibody (aPD-L1) on its shell through a matrix metalloproteinase-2 (MMP-2) substrate peptide, and incorporated "hidden" mannose in its sublayer. Through aPD-L1-mediated active targeting of tumor cells and tumor-infiltrating APCs, the nanodrug efficiently accumulated in tumor sites. Then, the PD-L1-conjugating peptide was cleaved by tumor-enriched MMP-2, leaving aPD-L1 on target cells for ICB while exposing mannose to mediate targeted delivery of ISD into tumor-infiltrating dendritic cells (DCs) and tumor-associated macrophages (TAMs). Activating the STING signaling in DCs and TAMs not only stimulated the APCs maturation to prime anti-tumor immunity but also induced their chemokine secretion to promote tumor infiltration of anti-tumor effector T cells, thus sensitizing TNBC to the ICB therapy. Consequently, a potent antitumor immunity was evoked to effectively inhibit the tumor growth and metastasis in mice bearing orthotopic 4T1 breast cancer, showing the great potential in treating immunologically "cold" tumors.
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Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Metaloproteinase 2 da Matriz , Antígeno B7-H1 , Manose , Interferons/farmacologia , Interferons/uso terapêutico , Microambiente Tumoral , Linhagem Celular TumoralRESUMO
Periodontitis is admittedly a microbe-driven intractable infectious disease, in which Porphyromonas gingivalis (Pg) plays a keystone role. Pg can selectively impair the antimicrobial responses of periodontal resident macrophages including their phagocytic and bactericidal activity without interfering their proinflammatory activity, which leads to microflora disturbance, destructive periodontal inflammation and alveolar bone loss eventually. Here, an injectable ROS-sensitive hydrogel is developed for releasing active bone marrow-derived macrophages (named ex-situ macrophages hereafter) and a complement C5a receptor antagonist (C5A) to the gingival crevice. Through appropriately tuning the hydrogel stiffness, the phagocytic activity of these macrophages is greatly enhanced, reaching an optimal performance at the elastic modulus of 106 kPa. Meanwhile, C5A avoids undesired C5a receptor activation by Pg to ensure the bacterial killing activity of both the ex-situ and in-situ macrophages. Besides, the ROS-sensitive hydrogels show another distinct feature of decreasing the ROS level in periodontal niche, which contributes to the alleviated periodontal inflammation and attenuated bone loss as well. This study highlights the potential of utilizing hydrogels with tailored biomechanical properties to remodel the functions of therapeutic cells, which is expected to find wide applications even beyond periodontitis treatment.
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Thermal ablation (TA) as an effective method treating hepatocellular carcinoma (HCC) in clinics is facing great challenges of high recurrence and metastasis. Although immune-checkpoint blockade (ICB)-based immunotherapy has shown potential to inhibit recurrence and metastasis, the combination strategy of ICB and thermal ablation has shown little progress in HCC treatments. The tremendous hurdle for combining ICB with thermal ablation lies with the insufficient antigen internalization and immaturity of tumor-infiltrating dendritic cells (TIDCs) which leads to an inferior immune response to distant tumor growth and metastasis. Herein, an antigen-capturing nanoplatform, whose surface was modified with mannose as a targeting ligand, was constructed for co-delivering tumor-associated antigens (TAAs) and m6A demethylases inhibitor (i.e., fat mass and obesity associated gene (FTO) inhibitor) into TIDCs. In vivo results demonstrate that the intratumoral injection of nanodrug followed by HCC thermal ablation promotes dendritic cells (DCs) maturation, improves tumor infiltration of effector T cells and generates immune memory, which synergize with ICB treatment to inhibit the distant tumor growth and lung metastasis. Therefore, the antigen-capturing and FTO-inhibiting nanodrug holds potential to boost the ICB-based immunotherapy against HCC after thermal ablation.
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Although small interfering RNA (siRNA) therapy has achieved great progress, unwanted gene inhibition in normal tissues severely limits its extensive clinical applications due to uncontrolled siRNA biodistribution. Herein, a spatially controlled siRNA activation strategy is developed to achieve tumor-specific siRNA therapy without gene inhibition in the normal tissues. The quaternary ammonium moieties are conjugated to amphiphilic copolymers via reactive oxygen species (ROS)-sensitive thioketal (TK) linkers for co-delivery of siRNA and photosensitizer chlorin e6 (Ce6), showing excellent siRNA complexation capacity and near infrared (NIR)-controlled siRNA release. In the normal tissue, siRNAs are trapped and degraded in the endo-lysosomes due to the unprotonatable property of quaternary ammonium moiety, showing the siRNA activity "off" state. When NIR irradiation is spatially applied to the tumor tissue, the NIR irradiation/Ce6-induced ROS trigger siRNA endo-lysosomal escape and cytosolic release through the photochemical internalization effect and cleavage of TK bonds, respectively, showing the siRNA activity "on" state. The siRNA-mediated glutathione peroxidase 4 gene inhibition enhances ROS accumulation. The synergistic antitumor activity of Ce6 photodynamic therapy and gene inhibition is confirmed in vivo. Spatially controlled tumor-specific siRNA activation and co-delivery with Ce6 using unprotonatable and ROS-sensitive cationic nanocarriers provide a feasible strategy for tumor-specific siRNA therapy with synergistic drug effects.
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Compostos de Amônio , Clorofilídeos , Nanopartículas , Fotoquimioterapia , Porfirinas , Linhagem Celular Tumoral , Nanopartículas/química , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Fármacos Fotossensibilizantes/química , Porfirinas/química , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Distribuição TecidualRESUMO
Oxaliplatin (OXA) is a first-line chemotherapeutic agent for treating colorectal cancer (CC). However, the chemotherapeutic effect of OXA on CC is limited by the M2-like polarization of tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) and protective autophagy of tumor cells. Here, a cationic polymer APEG-PAsp(PEI) (PAPEI) was prepared to deliver small-interfering RNA (siRNA) to silence the lactate dehydrogenase A (LDHA) gene (LDHA-siRNA) to enhance the chemotherapeutic effect of OXA on CC. The PAPEI/LDHA-siRNA nanocomplex effectively silenced the LDHA gene to inhibit the secretion of lactic acid from tumor cells, resulting in inhibition of the M2-like polarization of TAMs. In addition, the nanocomplex also amplified OXA-induced autophagy and transformed protective autophagy into autophagic death. Consequently, the combination treatment of OXA and PAPEI/LDHA-siRNA showed a dramatically increased chemotherapeutic effect on CC compared with the OXA-alone treatment, which also suggested its attractive potential for treating CC-like immune "cold" tumors.
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Neoplasias Colorretais , Nanopartículas , Autofagia , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Humanos , Lactato Desidrogenase 5 , Nanopartículas/uso terapêutico , Oxaliplatina/farmacologia , RNA Interferente Pequeno/farmacologia , Microambiente Tumoral , Macrófagos Associados a TumorRESUMO
A majority of cancers fail to respond to immunotherapy due to the immunosuppressive tumor microenvironment (TME), and metabolic regulation of the TME has been a promising strategy to improve immunotherapy. Lactate is a key metabolic player in tumor immune response since its excess secretion aggravates tumor immune escape by favoring the polarization of tumor-associated macrophages (TAMs) to an immunosuppressive phenotype meanwhile impeding the tumor infiltration of the cytotoxic T lymphocyte. Here, we proposed a metabolic reprogramming mechanism to ameliorate tumor immunosuppression by using lonidamine and syrosingopine incorporated liposomes (L@S/L) to regulate lactate production and efflux. Concretely, lonidamine reduced lactate production by affecting the glycolytic metabolic pathway while syrosingopine decreased lactate efflux by inhibiting the key protein expression of the lactate transporter MCT-4. Consequently, both the drugs synergistically normalize the pH of the TME to overcome the tumor immunosuppressive microenvironment. In vivo studies demonstrated that the decreased extracellular lactate preferentially polarized TAMs to the M1 phenotype, simultaneously increased the proportion of NK cells and reduced the number of Treg cells. These results validated an efficient tumor immunotherapy in the breast cancer model. This new strategy of lactic acid metabolism regulation is proposed to operate in concert with immune modulation in the TME, which shows great potential for immunotherapy of immunologically "cold" tumors.
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Nanopartículas , Neoplasias , Humanos , Fatores Imunológicos , Imunoterapia/métodos , Ácido Láctico , Nanopartículas/uso terapêutico , Neoplasias/patologia , Microambiente TumoralRESUMO
One of the main challenges in applying the immune checkpoint blockade to treat colorectal cancer (CRC) is the immunosuppressive tumor microenvironment. Owing to its excellent cancer cell killing ability and immune activation, mild photothermal therapy (PTT) has shown bright promise to sensitize tumors to immune checkpoint inhibition through turning the immunologically "cold" tumors into "hot" ones. Herein, a mild photothermal effect-assisted theragnostic nanodrug (MnO2@MPDA-PEG NPs) is developed by incorporating MnO2 into PEGylated-mesoporous polydopamine nanoparticles (MPDA-PEG NPs). The presence of PEG endows the theragnostic nanodrug with high biostability. After accumulation in colorectal tumor, the theragnostic nanodrug responds to the tumor microenvironment, leading to the simultaneous release of Mn2+ which serves as a magnetic resonance imaging (MRI) contrast agent for tumor imaging. The released Mn2+ could also promote mild photothermal treatment-induced immune response, including the maturation of BMDC cells. In vivo antitumor studies on a CT26 model demonstrate that MnO2@MPDA-PEG NPs could be a promising dual-imaging theragnostic nanodrug to potentiate the systemic antitumor immunities.
Assuntos
Neoplasias Colorretais , Nanopartículas , Linhagem Celular Tumoral , Neoplasias Colorretais/terapia , Meios de Contraste , Humanos , Imunoterapia , Indóis , Compostos de Manganês , Óxidos , Fototerapia/métodos , Polímeros , Microambiente TumoralRESUMO
Recent breakthroughs in cell membrane-fabricated nanovaccine offer innovateive therapeutic options for preventing tumor metastasies and recurrence, yet the treatment of patient-specific solid tumor remained challenging owing to the immunosuppressive tumor microenvironment. Herein, we developed a personalized photothermal nanovaccine based on the surgical tumor-derived cell membranes (CMs) coating resiquimod (R848) loaded mesoporous polydopamine (MPDA) nanoparticles for targeting tumor photothermal immunotherapy and prevention. The fabricated photothermal nanovaccine MPDA-R848@CM (MR@C) demonstrates outstanding imaging-guided photothermal immunotherapy efficacy to eradicate solid tumors under near-IR laser irradiation and further inhibiting metastasis tumors by the resulted antitumor immunities, especially in combination with programmed death-ligand 1 antibody therapy (aPD-L1). Furthermore, from in vivo prophylactic testing results, it is confirmed that the 4T1 cells rechallenge can be prevented 100% in postsurgical tumor model after vaccination of the photothermal nanovaccine. Our work fabricates a personalized photothermal nanovaccine that possesses great potential for tumor-specific treatment and for preventing postoperative tumor recurrence.