Platelet-Drug Conjugates Engineered via One-step Fusion Approach for Metastatic and Postoperative Cancer Treatment.

The exploration of cell-based drug delivery systems for cancer therapy has gained growing attention. Approaches to engineering therapeutic cells with multidrug loading in an effective, safe, and precise manner while preserving their inherent biological properties remain of great interest. Here, we report a strategy to simultaneously load multiple drugs in platelets in a one-step fusion process. We demonstrate doxorubicin (DOX)-encapsulated liposomes conjugated with interleukin-15 (IL-15) could fuse with platelets to achieve both cytoplasmic drug loading and surface cytokine modification with a loading efficiency of over 70 % within minutes. Due to their inherent targeting ability to metastatic cancers and postoperative bleeding sites, the engineered platelets demonstrated a synergistic therapeutic effect to suppress lung metastasis and postoperative recurrence in mouse B16F10 melanoma tumor models.

Lyophilized lymph nodes for improved delivery of chimeric antigen receptor T cells.

Lymph nodes are crucial organs of the adaptive immune system, orchestrating T cell priming, activation and tolerance. T cell activity and function are highly regulated by lymph nodes, which have a unique structure harbouring distinct cells that work together to detect and respond to pathogen-derived antigens. Here we show that implanted patient-derived freeze-dried lymph nodes loaded with chimeric antigen receptor T cells improve delivery to solid tumours and inhibit tumour recurrence after surgery. Chimeric antigen receptor T cells can be effectively loaded into lyophilized lymph nodes, whose unaltered meshwork and cytokine and chemokine contents promote chimeric antigen receptor T cell viability and activation. In mouse models of cell-line-derived human cervical cancer and patient-derived pancreatic cancer, delivery of chimeric antigen receptor T cells targeting mesothelin via the freeze-dried lymph nodes is more effective in preventing tumour recurrence when compared to hydrogels containing T-cell-supporting cytokines. This tissue-mediated cell delivery strategy holds promise for controlled release of various cells and therapeutics with long-term activity and augmented function.

Rationally designed approaches to augment CAR-T therapy for solid tumor treatment.

Chimeric antigen receptor T cell denoted as CAR-T therapy has realized incredible therapeutic advancements for B cell malignancy treatment. However, its therapeutic validity has yet to be successfully achieved in solid tumors. Different from hematological cancers, solid tumors are characterized by dysregulated blood vessels, dense extracellular matrix, and filled with immunosuppressive signals, which together result in CAR-T cells' insufficient infiltration and rapid dysfunction. The insufficient recognition of tumor cells and tumor heterogeneity eventually causes cancer reoccurrences. In addition, CAR-T therapy also raises safety concerns, including potential cytokine release storm, on-target/off-tumor toxicities, and neuro-system side effects. Here we comprehensively review various targeting aspects, including CAR-T cell design, tumor modulation, and delivery strategy. We believe it is essential to rationally design a combinatory CAR-T therapy via constructing optimized CAR-T cells, directly manipulating tumor tissue microenvironments, and selecting the most suitable delivery strategy to achieve the optimal outcome in both safety and efficacy.

Inhibition of Tumor Metastasis by Liquid-Nitrogen-Shocked Tumor Cells with Oncolytic Viruses Infection.

Despite the superior tumor lytic efficacy of oncolytic viruses (OVs), their systemic delivery still faces the challenges of limited circulating periods, poor tumor tropism, and spontaneous antiviral immune responses. Herein, a virus-concealed tumor-targeting strategy enabling OVs' delivery toward lung metastasis via systemic administration is described. The OVs can actively infect, be internalized, and cloak into tumor cells. Then the tumor cells are subsequently treated with liquid-nitrogen-shocking to eliminate the pathogenicity. Such a Trojan Horse-like vehicle avoids virus neutralization and clearance in the bloodstream and facilitates tumor-targeted delivery for more than 110-fold virus enrichment in the tumor metastasis. In addition, this strategy can serve as a tumor vaccine and initiate endogenous adaptive antitumor effects through increasing the memory T cells and modulating the tumor immune microenvironment, including reducing the M2 macrophage, downregulating Treg cells, and priming T cells.

Engineered bacteria for augmented in situ tumor vaccination.

In situ tumor vaccination has aroused tremendous interest with its capability for eliciting strong and systemic antitumor immune responses. Unlike traditional cancer vaccines, in situ tumor vaccination avoids the laborious process of tumor antigen identification and can modulate tumor immunosuppressive microenvironment at the same time. In recent years, bacteria have been used as both efficient tumor-targeted delivery vehicles and potent adjuvants. Regarding the rapid development in this area, in this review, we summarize recent advances in the application of bacteria for in situ cancer vaccination. We illustrate the mechanisms of bacteria as both efficient tumor immunogenic cell death inducers and tumor-targeted delivery platforms. Then we comprehensively review the engineering strategies for designing bacteria-based in situ vaccination, including chemical modification, nanotechnology, and genetic engineering. The current dilemma and future directions are discussed at the end of this review.

Engineered NanoAlum from aluminum turns cold tumor hot for potentiating cancer metalloimmunotherapy.

The poor cancer immunotherapy outcome has been closely related to immunosuppressive tumor microenvironment (TME), which usually inactivates the antitumor immune cells and leads to immune tolerance. Metalloimmunotherapy by supplementing nutritional metal ions into TME has emerged as a potential strategy to activate the tumor-resident immune cells. Herein, we engineered a magnesium-contained nano-aluminum adjuvant (NanoAlum) through hydrolyzing a mixture of Mg(OH)2 and Al(OH)3, which has highly similar components to commercial Imject Alum. Peritumoral injection of NanoAlum effectively neutralized the acidic TME while releasing Mg2+ to activate the tumor-resident T cells. Meanwhile, NanoAlum also blocked the autophagy pathway in tumor cells and subsequently induced cell apoptosis. The in vivo studies showed that merely peritumoral injection of NanoAlum successfully inhibited the growth of solid tumors in mice. On this basis, NanoAlum combined with chemical drug methotrexate or immunomodulatory adjuvant CpG further induced potent antigen-specific antitumor immunity. Overall, our study first provides a rational design for engineering tumor-targeted nanomodulator from clinical adjuvants to achieve effective cancer metalloimmunotherapy against solid tumors.

Recent advances of bioresponsive polymeric nanomedicine for cancer therapy.

A bioresponsive polymeric nanocarrier for drug delivery is able to alter its physical and physicochemical properties in response to a variety of biological signals and pathological changes, and can exert its therapeutic efficacy within a confined space. These nanosystems can optimize the biodistribution and subcellular location of therapeutics by exploiting the differences in biochemical properties between tumors and normal tissues. Moreover, bioresponsive polymer-based nanosystems could be rationally designed as precision therapeutic platforms by optimizing the combination of responsive elements and therapeutic components according to the patient-specific disease type and stage. In this review, recent advances in smart bioresponsive polymeric nanosystems for cancer chemotherapy and immunotherapy will be summarized. We mainly discuss three categories, including acidity-sensitive, redox-responsive, and enzyme-triggered polymeric nanosystems. The important issues regarding clinical translation such as reproducibility, manufacture, and probable toxicity, are also commented.

Cell delivery devices for cancer immunotherapy.

Adoptive cell therapy (ACT) that leverages allogeneic or autologous immune cells holds vast promise in targeted cancer therapy. Despite the tremendous success of ACT in treating hematopoietic malignancies, its efficacy is limited in eradicating solid tumors via intravenous infusion of immune cells. With the extending technology of cancer immunotherapy, novel delivery strategies have been explored to improve the therapeutic potency of adoptively transferred cells for solid tumor treatment by innovating the administration route, maintaining the cell viability, and normalizing the tumor microenvironment. In this review, a variety of devices for cell delivery are summarized. Perspectives and challenges of cell delivery devices for cancer immunotherapy are also discussed.

TAM-targeted reeducation for enhanced cancer immunotherapy: Mechanism and recent progress.

Tumor-associated macrophage (TAM) as an important component of tumor microenvironment (TME) are closely related with the occurrence, development, and metastasis of malignant tumors. TAMs are generally identified as two distinct functional populations in TME, i.e., inflammatory/anti-tumorigenic (M1) and regenerative/pro-tumorigenic (M2) phenotype. Evidence suggests that occupation of the TME by M2-TAMs is closely related to the inactivation of anti-tumor immune cells such as T cells in TME. Recently, efforts have been made to reeducate TAMs from M2- to M1- phenotype to enhance cancer immunotherapy, and great progress has been made in realizing efficient modulation of TAMs using nanomedicines. To help readers better understand this emerging field, the potential TAM reeducation targets for potentiating cancer immunotherapy and the underlying mechanisms are summarized in this review. Moreover, the most recent advances in utilizing nanomedicine for the TAM immunomodulation for augmented cancer immunotherapy are introduced. Finally, we conclude with our perspectives on the future development in this field.

A Peritumorally Injected Immunomodulating Adjuvant Elicits Robust and Safe Metalloimmunotherapy against Solid Tumors.

Clinical immunotherapy of solid tumors elicits durable responses only in a minority of patients, largely due to the highly immunosuppressive tumor microenvironment (TME). Although rational combinations of vaccine adjuvants with inflammatory cytokines or immune agonists that relieve immunosuppression represent an appealing therapeutic strategy against solid tumors, there are unavoidable nonspecific toxicities due to the pleiotropy of cytokines and undesired activation of off-target cells. Herein, a Zn2+ doped layered double hydroxide (Zn-LDH) based immunomodulating adjuvant, which not only relieves immunosuppression but also elicits robust antitumor immunity, is reported. Peritumorally injected Zn-LDH sustainably neutralizes acidic TME and releases abundant Zn2+ , promoting a pro-inflammatory network composed of M1-tumor-associated macrophages, cytotoxic T cells, and natural-killer cells. Moreover, the Zn-LDH internalized by tumor cells effectively disrupts endo-/lysosomes to block autophagy and induces mitochondrial damage, and the released Zn2+ activates the cGas-STING signaling pathway to induce immunogenic cell death, which further promotes the release of tumor-associated antigens to induce antigen-specific cytotoxic T lymphocytes. Unprecedentedly, merely injection of Zn-LDH adjuvant, without using any cytotoxic inflammatory cytokines or immune agonists, significantly inhibits the growth, recurrence, and metastasis of solid tumors in mice. This study provides a rational bottom-up design of potent adjuvant for cancer metalloimmunotherapy against solid tumors.

The Roles of Mesenchymal Stem Cells in Gastrointestinal Cancers.

Mesenchymal stem cells (MSCs) were reported to have strong immunomodulatory ability, and inhibit the proliferation of T cells and their immune response through cell-to-cell interactions and the generation of cytokines. With high differentiation potential and self-renewal ability, MSCs are considered to function in alleviating inflammatory responses, promoting tissue regeneration and inhibiting tissue fibrosis formation. As the most common malignancies, gastrointestinal (GI) cancers have high incidence and mortality. The accurate diagnosis, exact prognosis and treatment of GI cancers have always been a hot topic. Therefore, the potential applications of MSCs in terms of GI cancers are receiving more and more attention. Recently, there is increasing evidence that MSCs may serve as a key point in the growth, metastasis, inhibition, treatment and prognosis of GI cancers. In this review, we summarized the roles of MSCs in GI cancers, mainly focusing on esophageal cancer (EC), gastric cancer (GC), liver cancer (LC), colorectal cancer (CRC) and pancreatic cancer. Besides, we proposed MSCs as potential targets and treatment strategies for the effective treatment of GI cancers, which may provide better guidance for the clinical treatment of GI cancers.

Gastrointestinal Cancers and Liver Cirrhosis: Implications on Treatments and Prognosis.

Liver cirrhosis tends to increase the risk in the management of gastrointestinal tumors. Patients with gastrointestinal cancers and liver cirrhosis often have serious postoperative complications and poor prognosis after surgery. Multiple studies have shown that the stage of gastrointestinal cancers and the grade of cirrhosis can influence surgical options and postoperative complications. The higher the stage of cancer and the poorer the degree of cirrhosis, the less the surgical options and the higher the risk of postoperative complications. Therefore, in the treatment of patients with gastrointestinal cancer and liver cirrhosis, clinicians should comprehensively consider the cancer stage, cirrhosis grade, and possible postoperative complications. This review summarizes the treatment methods of patients with different gastrointestinal cancer complicated with liver cirrhosis.

Recent Advances of Nanotechnology-Facilitated Bacteria-Based Drug and Gene Delivery Systems for Cancer Treatment.

Cancer is one of the most devastating and ubiquitous human diseases. Conventional therapies like chemotherapy and radiotherapy are the most widely used cancer treatments. Despite the notable therapeutic improvements that these measures achieve, disappointing therapeutic outcome and cancer reoccurrence commonly following these therapies demonstrate the need for better alternatives. Among them, bacterial therapy has proven to be effective in its intrinsic cancer targeting ability and various therapeutic mechanisms that can be further bolstered by nanotechnology. In this review, we will discuss recent advances of nanotechnology-facilitated bacteria-based drug and gene delivery systems in cancer treatment. Therapeutic mechanisms of these hybrid nanoformulations are highlighted to provide an up-to-date understanding of this emerging field.

Recent Advances of Cell Membrane Coated Nanoparticles in Treating Cardiovascular Disorders.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide, causing approximately 17.9 million deaths annually, an estimated 31% of all deaths, according to the WHO. CVDs are essentially rooted in atherosclerosis and are clinically classified into coronary heart disease, stroke and peripheral vascular disorders. Current clinical interventions include early diagnosis, the insertion of stents, and long-term preventive therapy. However, clinical diagnostic and therapeutic tools are subject to a number of limitations including, but not limited to, potential toxicity induced by contrast agents and unexpected bleeding caused by anti-platelet drugs. Nanomedicine has achieved great advancements in biomedical area. Among them, cell membrane coated nanoparticles, denoted as CMCNPs, have acquired enormous expectations due to their biomimetic properties. Such membrane coating technology not only helps avoid immune clearance, but also endows nanoparticles with diverse cellular and functional mimicry. In this review, we will describe the superiorities of CMCNPs in treating cardiovascular diseases and their potentials in optimizing current clinical managements.

Dynamic nanoassemblies for imaging and therapy of neurological disorders.

The past decades have witnessed an increased incidence of neurological disorders (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, ischemic stroke, and epilepsy, which significantly lower patients' life quality and increase the economic and social burden. Recently, nanomedicines composed of imaging and/or therapeutic agents have been explored to diagnose and/or treat NDs due to their enhanced bioavailability, blood-brain barrier (BBB) permeability, and targeting capacity. Intriguingly, dynamic nanoassemblies self-assembled from functional nanoparticles to simultaneously interfere with multiple pathogenic substances and pathological changes, have been regarded as one of the foremost candidates to improve the diagnostic and therapeutic efficacy of NDs. To help readers better understand this emerging field, in this review, the pathogenic mechanism of different types of NDs is briefly introduced, then the functional nanoparticles used as building blocks in the construction of dynamic nanoassemblies for NDs theranostics are summarized. Furthermore, dynamic nanoassemblies that can actively cross the BBB to target brain lesions, sensitively and efficiently diagnose or treat NDs, and effectively promote neuroregeneration are highlighted. Finally, we conclude with our perspectives on the future development in this field.

Acidic Mesoporous Zeolite ZSM-5 Supported Cu Catalyst with Good Catalytic Performance in the Hydroxysulfurization of Styrenes with Disulfides.

Development of highly active heterogeneous catalysts is an effective strategy for modern organic synthesis chemistry. In this work, acidic mesoporous zeolite ZSM-5 (HZSM-5-M), acidic-free mesoporous zeolite TS-1 (TS-1-M), and basic ETS-10 zeolite supported metal Cu catalysts were prepared to investigate their catalytic performances in the hydroxysulfurization of styrenes with diaryl disulfides. The effect of pore size and acidities of the supports, as well as the Cu species electronic properties of the catalysts on reaction activity were investigated. The results show that Cu⁺ and Cu2+ binded on HZSM-5-M show the highest activity and product selectivity for the desired ß-hydroxysulfides compounds.