Multifunctional hybrid exosomes enhanced cancer chemo-immunotherapy by activating the STING pathway.

Due to the immunosuppressive tumor microenvironment (ITM) resulting from tumor-associated macrophages (TAMs) and regulatory T cells, immune checkpoint blockade and vaccine therapies often lead to an inadequate immune response. Recently, cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon gene (cGAS/STING)-mediated innate immunity has emerged as a promising cancer therapeutic, as STING pathway activation could promote dendritic cells (DCs) maturation and tumor-specific cytotoxic T lymphocyte (CTL) and natural killer (NK) cell infiltration. Herein, multifunctional hybrid exosomes for cGAS/STING activation are designed by fusing genetically engineered exosomes carrying CD47 derived from tumor cells with exosomes from M1 macrophages, which are further encapsulated with DNA-targeting agent (SN38) and STING-agonist (MnO2). The hybrid exosomes demonstrate great tumor-targeting capacity and prolong blood circulation time due to the surface decoration of CD47. At the tumor site, the hybrid exosomes induce TAMs polarization to the M1 phenotype and release SN38 to induce DNA damage and Mn2+ to stimulate cGAS/STING activation. Furthermore, the resulting multifunctional hybrid exosomes (SN/Mn@gHE) promote DCs maturation and facilitate CTL infiltration and NK cell recruitment to the tumor region, leading to significant anti-tumor and antimetastatic efficacy. Our study suggests a novel strategy to enhance cancer immunotherapy by activating the STING pathway and ameliorating ITM.

Bilayer hydrogel dressing with lysozyme-enhanced photothermal therapy for biofilm eradication and accelerated chronic wound repair.

Biofilms are closely associated with the tough healing and dysfunctional inflammation of chronic wounds. Photothermal therapy (PTT) emerged as a suitable alternative which could destroy the structure of biofilms with local physical heat. However, the efficacy of PTT is limited because the excessive hyperthermia could damage surrounding tissues. Besides, the difficult reserve and delivery of photothermal agents makes PTT hard to eradicate biofilms as expectation. Herein, we present a GelMA-EGF/Gelatin-MPDA-LZM bilayer hydrogel dressing to perform lysozyme-enhanced PTT for biofilms eradication and a further acceleration to the repair of chronic wounds. Gelatin was used as inner layer hydrogel to reserve lysozyme (LZM) loaded mesoporous polydopamine (MPDA) (MPDA-LZM) nanoparticles, which could rapidly liquefy while temperature rising so as to achieve a bulk release of nanoparticles. MPDA-LZM nanoparticles serve as photothermal agents with antibacterial capability, could deeply penetrate and destroy biofilms. In addition, the outer layer hydrogel consisted of gelatin methacryloyl (GelMA) and epidermal growth factor (EGF) promoted wound healing and tissue regeneration. It displayed remarkable efficacy on alleviating infection and accelerating wound healing in vivo. Overall, the innovative therapeutic strategy we came up with has significant effect on biofilms eradication and shows promising application in promoting the repair of clinical chronic wounds.

Recapitulation of dynamic nanoparticle transport around tumors using a triangular multi-chamber tumor-on-a-chip.

3D tumor models are emerging as valuable tools for drug screening and nanoparticle based personalized cancer treatments. The main challenges in building microfluidic chip-based 3D tumor models currently include the development of bioinks with high bioactivity and the reproduction of the key tumor extracellular matrix (ECM) with heterogeneous tumor microenvironments. In this study, we designed a triangular multi-chamber tumor-on-a-chip (TM-CTC) platform, which consisted of three circular chambers at the vertices of a triangle connected by three rectangular chambers; it significantly improved the culture efficiency of 3D tumor tissues. MCF-7 tumor cells were cultured in a 3D ECM and then dynamically perfused for 7 days of culture to obtain abundant tumor spheroids with uniform size (100 ± 4.1 µm). The biological features of the 3D tumor tissue including epithelial transformation (EMT), hypoxia and proliferation activities were reproduced in the triangular multi-chamber tumor-on-a-chip (TM-CTC) platform. The permeability results of NPs confirmed that the ECM exhibited a significant barrier effect on the transportation of NPs when compared with free drugs, indicating that the ECM barrier should be considered as one of the key factors of drug delivery carrier development. In addition, this TM-CTC model provided a suitable platform for constructing a complex heterogeneous tumor microenvironment with multiple cells (MCF-7, HUVEC and MRC-5) involved, which was beneficial for exploring the dynamic interaction between tumor cells and other cells in the tumor microenvironment. The above results suggest that this TM-CTC model can simulate the dynamic transportation of NPs around 3D tumor tissues, and thus provide a reliable platform for NP evaluation.

3D bioprinted tumor model with extracellular matrix enhanced bioinks for nanoparticle evaluation.

The traditional evaluation of nanoparticles (NPs) is mainly based on 2D cell culture and animal models. However, these models are difficult to accurately represent human tumor microenvironment (TME) and fail to systematically study the complex transportation of NPs, thus limiting the translation of nano-drug formulations to clinical studies. This study reports a tumor model fabricated via 3D bioprinting with adipose decellularized extracellular matrix (ECM) enhanced hybrid bioink. Compared with 2D cultured cells, the 3D printed tumor models with multicellular spheroids formation are closer to real tumor in protein, gene expression and tumorigenicity bothin vitroandin vivo. Two characteristics of TME, ECM remodeling and epithelial-mesenchymal transition, are tracked simultaneously under 3D conditions. Furthermore, the cellular uptake efficiency of two different NPs is significantly lower in the printed 3D tumor model than the 2D individual cells, and higher drug resistance is observed in 3D group, which suggest the ECM barrier of tumor can significantly affect the permeability of NPs. These results suggest that this 3D printed tumor model is capable of mimicking the multiple TME, potentially providing a more accurate platform for the design and development of NPs before moving into animal and clinical trials.

3D printed heterogeneous hybrid hydrogel scaffolds for sequential tumor photothermal-chemotherapy and wound healing.

Surgical resection remains the mainstay of melanoma treatment. However, due to the difficulties in controlling tumor recurrence and wound healing simultaneously, high postoperative recurrence rates and wound reconstruction remain the most significant challenges. As a result, a heterogeneous hybrid hydrogel scaffold was designed in this work to achieve sequential photothermal therapy and chemotherapy for melanoma recurrence inhibition and wound healing. A 3D printing platform was used to create a SA-GG@PDA hybrid hydrogel scaffold, which was prepared from a hybrid bioink consisting of sodium alginate (SA), gellan gum (GG), and polydopamine nanoparticles (PDA NPs). The printability, biocompatibility, and mechanical qualities of the hybrid bioink were all satisfactory. PDA NPs were generated in situ in the hybrid bioink, providing superior photothermal effects to the scaffold. After coating with a thermosensitive gelatin hydrogel loaded with the chemotherapeutic drug doxorubicin (DOX), the heterogeneous hydrogel scaffold could accelerate drug release under photothermal triggering and achieve photothermal-chemotherapy to suppress tumor cell proliferation and recurrence after surgical resection. Subsequently, the printed porous hybrid hydrogel scaffold enhanced HUVEC proliferation and migration, as well as tissue ingrowth, promoting wound healing following surgery. In the same mouse model, the sequential treatment with the heterogeneous SA-GG@PDA + DOX hydrogel scaffold was tested. The fabrication of the heterogeneous SA-GG@PDA + DOX hydrogel scaffold with multifunctional capabilities seemed to be a potential technique for preventing tumor recurrence and promoting wound healing following surgery.