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Cancer metastasis and recurrence remain the leading causes of cancer-related mortality, and lung is a major metastatic anatomical location. Chimeric antigen receptor macrophages (CAR-M) represent promising candidates for cancer therapy owing to their superior tumour-infiltrating and antigen-specific phagocytotic abilities, and to being professional antigen presenting cells. However, broader applications of CAR-Ms face challenges such as complex manufacturing processes and predominant accumulation in the liver following intravenous administration. Here we present an inhalable engineered small extracellular vesicle (sEV), which contains mesothelin-specific CAR messenger RNA (CAR mRNA @aCD206 sEVs) for in situ generation of CAR-Ms. The sEVs are surface-integrated with anti-CD206 single-chain variable fragments (scFv) to target CD206-expressing, immunosuppressive (M2 phenotype) macrophages. The results in mouse models suggest that inhaled CAR mRNA @aCD206 sEVs could accumulate in lung tissue and deliver CAR mRNA specifically to macrophages, facilitating in situ CAR-M production. In a lung metastasis model, inhaled CAR mRNA @aCD206 sEVs effectively inhibit tumor growth and prime long-term memory immunity to prevent tumour recurrence. Collectively, our engineered sEV delivery platform demonstrates capability to selectively deliver CAR mRNA to macrophages in lung tissue, providing a promising immunotherapy strategy to effectively combat lung metastasis and recurrence via generation of CAR-Ms in situ. Chimeric antigen receptor (CAR) macrophages may represent a promising anti-cancer immune therapy strategy due to their favourable biological properties but in vitro manipulation and targeting to specific organs could be challenging. Here authors use inhalable small extracellular vesicles to deliver the CAR mRNA construct to macrophages in the lung and show that the thus in situ generated CAR macrophages successfully combat lung metastasis and cancer recurrence in a mouse model.

Background Chimeric antigen receptor (CAR) -T cell therapy is an efficient therapeutic strategy for specific hematologic malignancies. However, positive outcomes of this novel therapy in treating solid tumors are curtailed by the immunosuppressive tumor microenvironment (TME), wherein signaling of the checkpoint programmed death-1 (PD-1)/PD-L1 directly inhibits T-cell responses. Although checkpoint-targeted immunotherapy succeeds in increasing the number of T cells produced to control tumor growth, the desired effect is mitigated by the action of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in the TME. Previous studies have confirmed that targeting triggering-receptor-expressed on myeloid cells 2 (TREM2) on TAMs and MDSCs enhances the outcomes of anti-PD-1 immunotherapy. Methods We constructed carcinoembryonic antigen (CEA)-specific CAR-T cells for colorectal cancer (CRC)-specific antigens with an autocrine PD-1-TREM2 single-chain variable fragment (scFv) to target the PD-1/PD-L1 pathway, MDSCs and TAMs. Results We found that the PD-1-TREM2-targeting scFv inhibited the activation of the PD-1/PD-L1 pathway. In addition, these secreted scFvs blocked the binding of ligands to TREM2 receptors present on MDSCs and TAMs, reduced the proportion of MDSCs and TAMs, and enhanced T-cell effector function, thereby mitigating immune resistance in the TME. PD-1-TREM2 scFv-secreting CAR-T cells resulted in highly effective elimination of tumors compared to that achieved with PD-1 scFv-secreting CAR-T therapy in a subcutaneous CRC mouse model. Moreover, the PD-1-TREM2 scFv secreted by CAR-T cells remained localized within tumors and exhibited an extended half-life. Conclusions Together, these results indicate that PD-1-TREM2 scFv-secreting CAR-T cells have strong potential as an effective therapy for CRC.

Background Non-small cell lung cancer (NSCLC) is a worldwide health threat with high annual morbidity and mortality. Chemotherapeutic drugs such as paclitaxel (PTX) have been widely applied clinically. However, systemic toxicity due to the non-specific circulation of PTX often leads to multi-organ damage, including to the liver and kidney. Thus, it is necessary to develop a novel strategy to enhance the targeted antitumor effects of PTX. Methods Here, we engineered exosomes derived from T cells expressing the chimeric antigen receptor (CAR-Exos), which targeted mesothelin (MSLN)-expressing Lewis lung cancer (MSLN-LLC) through the anti-MSLN single-chain variable fragment (scFv) of CAR-Exos. PTX was encapsulated into CAR-Exos (PTX@CAR-Exos) and administered via inhalation to an orthotopic lung cancer mouse model. Results Inhaled PTX@CAR-Exos accumulated within the tumor area, reduced tumor size, and prolonged survival with little toxicity. In addition, PTX@CAR-Exos reprogrammed the tumor microenvironment and reversed the immunosuppression, which was attributed to infiltrating CD8 + T cells and elevated IFN-γ and TNF-α levels. Conclusions Our study provides a nanovesicle-based delivery platform to promote the efficacy of chemotherapeutic drugs with fewer side effects. This novel strategy may ameliorate the present obstacles to the clinical treatment of lung cancer.

Suppression of chimeric antigen receptor-modified T (CAR-T) cells by the immunosuppressive tumor microenvironment remains a major barrier to their efficacy against solid tumors. To address this, we develop an anti-PD-L1-expressing nanovesicle loaded with the STING agonist cGAMP (aPD-L1 NVs@cGAMP) to remodel the tumor microenvironment and thereby enhance CAR-T cell activity. Following pulmonary delivery, the nanovesicles rapidly accumulate in the lung and selectively deliver STING agonists to PD-L1-overexpressing cells via the PD-1/PD-L1 interaction. This targeted delivery effectively avoids the systemic inflammation and poor cellular uptake that plague free STING agonists. Internalized STING agonists trigger STING signaling and induce interferon responses, which diminish immunosuppressive cell populations such as myeloid-derived suppressor cells in the tumor microenvironment and promote CAR-T cell infiltration. Importantly, the anti-PD-L1 single chain variable fragment on the nanovesicle surface blocks PD-L1 upregulation induced by STING agonists and prevents CAR-T cell exhaustion. In both orthotopic lung cancer and lung metastasis model, combined therapy with CAR-T cells and aPD-L1 NVs@cGAMP potently inhibits tumor growth and prevents recurrence. Therefore, aPD-L1 NVs@cGAMP is expected to serve as an effective CAR-T cell enhancer to improve the efficacy of CAR-T cells against solid tumors. The efficacy of CAR-T cells is hindered by the immunosuppressive microenvironment of solid tumors. Here the authors report the design and characterization of anti-PD-L1-expressing inhalable nanovesicles loaded with the STING agonist cGAMP, showing enhanced CAR-T cell activity in both orthotopic lung cancer and lung metastasis models.

Background The worldwide pandemic of COVID-19 remains a serious public health menace as the lack of efficacious treatments. Cytokine storm syndrome (CSS) characterized with elevated inflammation and multi-organs failure is closely correlated with the bad outcome of COVID-19. Hence, inhibit the process of CSS by controlling excessive inflammation is considered one of the most promising ways for COVID-19 treatment. Results Here, we developed a biomimetic nanocarrier based drug delivery system against COVID-19 via anti-inflammation and antiviral treatment simultaneously. Firstly, lopinavir (LPV) as model antiviral drug was loaded in the polymeric nanoparticles (PLGA-LPV NPs). Afterwards, macrophage membranes were coated on the PLGA-LPV NPs to constitute drugs loaded macrophage biomimetic nanocarriers (PLGA-LPV@M). In the study, PLGA-LPV@M could neutralize multiple proinflammatory cytokines and effectively suppress the activation of macrophages and neutrophils. Furthermore, the formation of NETs induced by COVID-19 patients serum could be reduced by PLGA-LPV@M as well. In a mouse model of coronavirus infection, PLGA-LPV@M exhibited significant targeted ability to inflammation sites, and superior therapeutic efficacy in inflammation alleviation and tissues viral loads reduction. Conclusion Collectively, such macrophage biomimetic nanocarriers based drug delivery system showed favorable anti-inflammation and targeted antiviral effects, which may possess a comprehensive therapeutic value in COVID-19 treatment.

Background Despite the success of chimeric antigen receptor (CAR)-T cell therapy in hematological malignancies, its efficacy against solid tumors like non-small cell lung cancer (NSCLC) remains limited due to the immunosuppressive tumor microenvironment (TME) and insufficient T-cell infiltration. Dendritic cell (DC) vaccines offer potential to remodel the TME but face challenges with targeted antigen delivery. Therefore, we want to develop a DC-targeted nanovesicle (NV) vaccine to enhance the antitumor activity of CAR-T cells against lung cancer. Results We engineered CD205-targeted nanovesicles (aCD205 NVs) derived from LLC cells displaying anti-CD205 single-chain variable fragments. These NVs were evaluated for DC targeting, maturation induction, and T cell priming in vitro and were injected intravenously with Poly(I: C) as a DC vaccine to reprogram the TME in vivo. The combinatorial effect with mesothelin (MSLN)-targeted CAR-T cells (CAR-T + Vac therapy) was assessed in subcutaneous and orthotopic murine LLC models. We found that CAR-T + Vac therapy significantly enhanced tumor infiltration of CAR-T cells and endogenous T cells, substantially elevated cytotoxic molecules (Granzyme B and Perforin), and pro-inflammatory cytokines (IFN-γ and TNF-α), while reducing immunosuppressive cell populations (M2 macrophages, MDSCs, and Tregs) and IL-10. This synergistic remodeling resulted in potent tumor suppression and markedly prolonged overall survival, with no observable short-term toxicity. Conclusions This study establishes a novel combinatorial strategy utilizing CD205-targeted, tumor cell-derived NVs as a DC vaccine to effectively reprogram the immunosuppressive TME. CAR-T + Vac therapy significantly enhances CAR-T cell infiltration and antitumor efficacy against lung cancer, providing a versatile and promising platform for advancing solid tumor immunotherapy. Graphical Abstract Schematic illustration of CAR-T + Vac therapy

The pandemic of coronavirus disease 2019 (COVID‐19) is continually worsening. Clinical treatment for COVID‐19 remains primarily supportive with no specific medicines or regimens. Here, the development of multifunctional alveolar macrophage (AM)‐like nanoparticles (NPs) with photothermal inactivation capability for COVID‐19 treatment is reported. The NPs, made by wrapping polymeric cores with AM membranes, display the same surface receptors as AMs, including the coronavirus receptor and multiple cytokine receptors. By acting as AM decoys, the NPs block coronavirus from host cell entry and absorb various proinflammatory cytokines, thus achieving combined antiviral and anti‐inflammatory treatment. To enhance the antiviral efficiency, an efficient photothermal material based on aggregation‐induced emission luminogens is doped into the NPs for virus photothermal disruption under near‐infrared (NIR) irradiation. In a surrogate mouse model of COVID‐19 caused by murine coronavirus, treatment with multifunctional AM‐like NPs with NIR irradiation decreases virus burden and cytokine levels, reduces lung damage and inflammation, and confers a significant survival advantage to the infected mice. Crucially, this therapeutic strategy may be clinically applied for the treatment of COVID‐19 at early stage through atomization inhalation of the NPs followed by NIR irradiation of the respiratory tract, thus alleviating infection progression and reducing transmission risk. A therapeutic strategy for COVID‐19, based on multifunctional alveolar macrophage (AM)‐like nanoparticles (NPs), is successfully developed. The NPs display various AM receptors for coronavirus neutralization and proinflammatory cytokines absorption, thus achieving combined antiviral and anti‐inflammatory treatment. Furthermore, the photothermal feature of the NPs facilitates virus disruption under near‐infrared irradiation. This multimodal therapeutic regimen may be clinically applied for COVID‐19 management. ​

Background Considering the threat of the COVID-19 pandemic, caused by SARS-CoV-2, there is an urgent need to develop effective treatments. At present, neutralizing antibodies and small-molecule drugs such as remdesivir, the most promising compound to treat this infection, have attracted considerable attention. However, some potential problems need to be concerned including viral resistance to antibody-mediated neutralization caused by selective pressure from a single antibody treatment, the unexpected antibody-dependent enhancement (ADE) effect, and the toxic effect of small-molecule drugs. Results Here, we constructed a type of programmed nanovesicle (NV) derived from bispecific CAR-T cells that express two single-chain fragment variables (scFv), named CR3022 and B38, to target SARS-CoV-2. Nanovesicles that express both CR3022 and B38 (CR3022/B38 NVs) have a stronger ability to neutralize Spike-pseudovirus infectivity than nanovesicles that express either CR3022 or B38 alone. Notably, the co-expression of CR3022 and B38, which target different epitopes of spike protein, could reduce the incidence of viral resistance. Moreover, the lack of Fc fragments on the surface of CR3022/B38 NVs could prevent ADE effects. Furthermore, the specific binding ability to SARS-CoV-2 spike protein and the drug loading capacity of CR3022/B38 NVs can facilitate targeted delivery of remdesiver to 293 T cells overexpressing spike protein. These results suggest that CR3022/B38 NVs have the potential ability to target antiviral drugs to the main site of viral infection, thereby enhancing the antiviral ability by inhibiting intracellular viral replication and reducing adverse drug reactions. Conclusions In summary, we demonstrate that nanovesicles derived from CAR-T cells targeting the spike protein of SARS-COV-2 have the ability to neutralize Spike-pseudotyped virus and target antiviral drugs. This novel therapeutic approach may help to solve the dilemma faced by neutralizing antibodies and small-molecule drugs in the treatment of COVID-19. Graphical Abstract

Chimeric antigen receptor T (CAR-T) cell therapy faces critical barriers in solid tumors, including poor infiltration, T cell exhaustion, and immunosuppressive microenvironments, resulting in response rates below 10%. Herein, we engineered an inhalable nanoplatform using induced pluripotent stem cell-derived exosomes (IEXOs) displaying bispecific PD-1/mesothelin (MSLN) single-chain variable fragments (scFv) and loaded with indole-3-propionic acid (IPA) for metabolic reprogramming. IEXOs demonstrated high yield and intrinsic antitumor properties, inhibiting Lewis lung carcinoma (LLC) cell proliferation and migration. The bispecific exosomes loaded with IPA (BIEXO@IPA) achieved efficient pulmonary delivery via nebulization with 79.3% tumor cell-specific uptake versus 47.9% for liposomes in orthotopic lung cancer models. BIEXO@IPA treatment reduced tumor burden by 87.9% and achieved 80% survival at 80 days. Mechanistically, BIEXO@IPA bridged PD-1 + T cells to MSLN + tumor cells through bispecific engagement while expanding progenitor exhausted T (Tpex) cells and reducing regulatory T cells. When combined with CAR-T cells, BIEXO@IPA achieved 66.7% complete remission with 100% survival at 80 days and 83.3% resistance to tumor rechallenge. Safety assessments revealed minimal toxicity. This BIEXO@IPA platform represents a scalable, clinically translatable strategy that addresses fundamental CAR-T limitations in solid tumors through synergistic multimodal immunomodulation. Graphical Abstract

Background: Myocardial infarction (MI) leads to cardiomyocyte death, poor cardiac remodeling, and heart failure, making it a major cause of mortality and morbidity. To restore cardiac pumping function, induction of cardiomyocyte regeneration has become a focus of academic interest. The Hippo pathway is known to regulate cardiomyocyte proliferation and heart size, and its inactivation allows adult cardiomyocytes to re-enter the cell cycle. Methods: In this study, we investigated whether exosomes from adipose-derived stem cells (ADSCs) could effectively transfer siRNA for the Hippo pathway regulator Salvador (SAV) into cardiomyocytes to induce cardiomyocyte regeneration in a mouse model of MI. Results: Our results showed that exosomes loaded with SAV-siRNA effectively transferred siRNA into cardiomyocytes and induced cardiomyocyte re-entry into the cell cycle, while retaining the previously demonstrated therapeutic efficacy of ADSC-derived exosomes to improve post-infarction cardiac function through anti-fibrotic, pro-angiogenic, and other effects. Conclusions: Our findings suggest that siRNA delivery via ADSC-derived exosomes may be a promising approach for the treatment of MI.