TADF-Guiding Modification of Endoplasmic Reticulum-Targeted Photosensitizers for Efficient Photodynamic Immunotherapy.

Pharmacological activation of the immunogenic cell death (ICD) pathway by endoplasmic reticulum (ER) targeted photosensitizer (PS) has become a promising strategy for tumor immunotherapy. Despite a clear demand for ER-targeted PS, the sluggish intersystem crossing (ISC) process, unstable excited state, insufficient ROS production, and immunosuppressive tumor microenvironment (ITME) combined to cause the high-efficiency agents are still limited. Herein, three groups commonly used in thermally activated delayed fluorescence (TADF) molecular design are used to modify the excited state characteristics of xanthene-based cyanine PS (obtained the XCy-based PS). The electronic and geometric modulation effectively optimize the excited state characteristics, facilitating the ISC process and prolonging the excited state life for boosting ROS generation. Among them, car-XCy showed 100 times longer excited state life and 225% higher ROS yield than that of original XCy. The satisfactory ROS production and ER-targeted ability of car-XCy arouse intense ER stress to activate the ICD. Adequate antigen presentation promotes the dendritic cell maturation and infiltration of cytotoxic T lymphocytes (CTLs), ultimately reversing the ITME to realize efficient immunotherapy. As a result, significant inhibition is observed in both primary and distant tumors, underscoring the efficacy of this TADF-guiding excited state characteristics modulation strategy for developing photodynamic immunotherapy drugs.

Revolutionizing cancer treatment: The power of cell-based drug delivery systems.

Intravenous administration of drugs is a widely used cancer therapy approach. However, the efficacy of these drugs is often hindered by various biological barriers, including circulation, accumulation, and penetration, resulting in poor delivery to solid tumors. Recently, cell-based drug delivery platforms have emerged as promising solutions to overcome these limitations. These platforms offer several advantages, including prolonged circulation time, active targeting, controlled release, and excellent biocompatibility. Cell-based delivery systems encompass cell membrane coating, intracellular loading, and extracellular backpacking. These innovative platforms hold the potential to revolutionize cancer diagnosis, monitoring, and treatment, presenting a plethora of opportunities for the advancement and integration of pharmaceuticals, medicine, and materials science. Nevertheless, several technological, ethical, and financial barriers must be addressed to facilitate the translation of these platforms into clinical practice. In this review, we explore the emerging strategies to overcome these challenges, focusing specifically on the functions and advantages of cell-mediated drug delivery in cancer treatment.

Structure-Activity Relationship of pH-Sensitive Doxorubicin-Fatty Acid Prodrug Albumin Nanoparticles.

Albumin has emerged as a versatile drug carrier. To harness albumin as a carrier for doxorubicin (DOX), we synthesized three acid-labile DOX prodrugs using stearic acid (SA), oleic acid (OA), and linoleic acid (LA) as the albumin-binding motif, respectively. Different from conventional albumin nanodrugs (such as Abraxane, with a drug loading of 10%), the DOX prodrugs assembled albumin nanoparticles (NPs) have an ultrahigh drug loading (>35%). Noteworthy, we demonstrated that the saturation of fatty acids exerted great influence on colloidal stability of prodrug NPs, thus affecting their in vivo pharmacokinetics, tumor accumulation and antitumor efficacy. Furthermore, the hydrazone bond-bridged DOX prodrugs could remain intact in the bloodstream but allow DOX to be released in the acidic tumor environment, resulting in improved antitumor efficacy and safety. Our work gives novel insights into the structure-to-efficacy relationship of albumin-bound fatty acid prodrugs and provides a simple strategy for advanced albumin-bound nanomedicines.

Critical roles of linker length in determining the chemical and self-assembly stability of SN38 homodimeric nanoprodrugs.

Homodimeric prodrug nanoassemblies (HDPNs) have been widely studied for efficient cancer therapy by virtue of their ultra-high drug loading and distinct nanostructure. However, the development of SN38 HDPNs is still a great challenge due to the rigid planar aromatic ring structure. Improving the structural flexibility of homodimeric prodrugs by increasing the linker length may be a potential strategy for constructing SN38 HDPNs. Herein, three SN38 homodimeric prodrugs with different linker lengths were synthesized. The number of carbon atoms from the disulfide bond to the adjacent ester bond is 1 (denoted as α-SN38-SS-SN38), 2 (ß-SN38-SS-SN38), and 3 (γ-SN38-SS-SN38), respectively. Interestingly, we found that α-SN38-SS-SN38 exhibited extremely low yield and poor chemical stability. Additionally, ß-SN38-SS-SN38 demonstrated suitable chemical stability but poor self-assembly stability. In comparison, γ-SN38-SS-SN38 possessed good chemical and self-assembly stability, thereby improving the tumor accumulation and antitumor efficacy of SN38. We developed the SN38 HDPNs for the first time and illustrated the underlying molecular mechanism of increasing the linker length to enhance the chemical and self-assembly stability of homodimeric prodrugs. These findings would provide new insights for the rational design of HDPNs with superior performance.

Probing the Role of Connecting Bonds and Modifying Chains in the Rational Design of Prodrug Nanoassemblies.

Prodrug-based self-assembled nanoparticles combined with the merits of nanotechnology and prodrugs strategies have gradually become a research trending topic in the field of drug delivery. These prodrugs usually consist of parent drugs, connecting bonds, and modifying chains. The influences of the connecting bonds and modifying chains on the pharmaceutical characteristics, in vivo delivery fate, and antitumor activity of prodrug nanoassemblies remain elusive. Herein, three docetaxel (DTX) prodrugs were designed using sulfur bonds (thioether bond or disulfide bond) as connecting bonds and fatty alcohols (straight chain or branched chain) as modifying chains. Interestingly, the difference between connecting bonds and modifying chains deeply influenced the colloidal stability, redox responsive drug release, cytotoxicity, pharmacokinetic properties, tumor accumulation, and antitumor effect of prodrug nanoassemblies. DTX conjugated with branched chain fatty alcohols via disulfide bonds (HUA-SS-DTX) significantly improved the antitumor efficiency of DTX and reduced the systematic toxicity. Our study elaborates on the vital role of connecting bonds and modifying chains in the rational design of prodrug nanoassemblies.

Hybrid chalcogen bonds in prodrug nanoassemblies provides dual redox-responsivity in the tumor microenvironment.

Sulfur bonds, especially trisulfide bond, have been found to ameliorate the self-assembly stability of homodimeric prodrug nanoassemblies and could trigger the sensitive reduction-responsive release of active drugs. However, the antitumor efficacy of homodimeric prodrug nanoassemblies with single reduction-responsivity may be restricted due to the heterogeneous tumor redox microenvironment. Herein, we replace the middle sulfur atom of trisulfide bond with an oxidizing tellurium atom or selenium atom to construct redox dual-responsive sulfur-tellurium-sulfur and sulfur-selenium-sulfur hybrid chalcogen bonds. The hybrid chalcogen bonds, especially the sulfur-tellurium-sulfur bond, exhibit ultrahigh dual-responsivity to both oxidation and reduction conditions, which could effectively address the heterogeneous tumor microenvironment. Moreover, the hybrid sulfur-tellurium-sulfur bond promotes the self-assembly of homodimeric prodrugs by providing strong intermolecular forces and sufficient steric hindrance. The above advantages of sulfur-tellurium-sulfur bridged homodimeric prodrug nanoassemblies result in the improved antitumor efficacy of docetaxel with satisfactory safety. The exploration of hybrid chalcogen bonds in drug delivery deepened insight into the development of prodrug-based chemotherapy to address tumor redox heterogeneity, thus enriching the design theory of prodrug-based nanomedicines.

Knockdown of 15-bp Deletion-Type v-raf Murine Sarcoma Viral Oncogene Homolog B1 mRNA in Pancreatic Ductal Adenocarcinoma Cells Repressed Cell Growth In Vitro and Tumor Volume In Vivo.

Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second-most common cause of death within the next 10 years. Due to the limited efficacy of available therapies, the survival rate of PDAC patients is very low. Oncogenic BRAF mutations are one of the major causes of PDAC, specifically the missense V600E and L485-P490 15-bp deletion mutations. Drugs targeting the V600E mutation have already been approved by the United States Food and Drug Administration. However, a drug targeting the deletion mutation at L485-P490 of the BRAF gene has not been developed to date. The BxPC-3 cell line is a PDAC-derived cell line harboring wild-type KRAS and L485-P490 deleted BRAF genes. These cells are heterozygous for BRAF, harboring both wild-type BRAF and BRAF with the 15-bp deletion. In this study, siRNA was designed for the targeted knockdown of 15-bp deletion-type BRAF mRNA. This siRNA repressed the phosphorylation of extracellular-signal-regulated kinase proteins downstream of BRAF and suppressed cell growth in vitro and in vivo. Furthermore, siRNAs with 2'-O-methyl modifications at positions 2-5 reduce the seed-dependent off-target effects, as confirmed by reporter and microarray analyses. Thus, such siRNA is a promising candidate therapy for 15-bp deletion-type BRAF-induced tumorigenesis.

Bioengineered Platelets Combining Chemotherapy and Immunotherapy for Postsurgical Melanoma Treatment: Internal Core-Loaded Doxorubicin and External Surface-Anchored Anti-PD-L1 Antibody Backpacks.

The pivotal factors affecting the survival rate of patients include metastasis and tumor recurrence after the resection of the primary tumor. Anti-PD-L1 antibody (aPD-L1) has promising efficacy but with some side effects for the off-target binding between aPD-L1 and normal tissues. Here, inspired by the excellent targeting capability of platelets with respect to tumor cells, we propose bioengineered platelets (PDNGs) with inner-loaded doxorubicin (DOX) and outer-anchored aPD-L1-cross-linked nanogels to reduce tumor relapse and metastatic spread postoperation. The cargo does not impair the normal physiological functions of platelets. Free aPD-L1 is cross-linked to form nanogels with a higher drug-loading efficiency and is sustainably released to trigger the T-cell-mediated destruction of tumor cells, reversing the tumor immunosuppressive microenvironment. PDNGs can reduce the postoperative tumor recurrence and metastasis rate, prolonging the survival time of mice. Our findings indicate that bioengineered platelets are promising in postsurgical cancer treatment by the tumor-capturing and in situ microvesicle-secreting capabilities of platelets.

Inhibition of post-surgery tumour recurrence via a sprayable chemo-immunotherapy gel releasing PD-L1 antibody and platelet-derived small EVs.

BACKGROUND: Melanoma is the most serious type of skin cancer, and surgery is an effective method to treat melanoma. Unfortunately, local residual micro-infiltrated tumour cells and systemic circulating tumour cells (CTCs) are significant causes of treatment failure, leading to tumour recurrence and metastasis. METHODS: Small EVs were isolated from platelets by differential centrifugation, and doxorubicin-loaded small EVs (PexD) was prepared by mixing small EVs with doxorubicin (DOX). PexD and an anti-PD-L1 monoclonal antibody (aPD-L1) were co-encapsulated in fibrin gel. The synergistic antitumour efficacy of the gel containing PexD and aPD-L1 was assessed both in vitro and in vivo. RESULTS: Herein, we developed an in situ-formed bioresponsive gel combined with chemoimmunotherapeutic agents as a drug reservoir that could effectively inhibit both local tumour recurrence and tumour metastasis. In comparison with a DOX solution, PexD could better bind to tumour cells, induce more tumour immunogenic cell death (ICD) and promote a stronger antitumour immune response. PexD could enter the blood circulation through damaged blood vessels to track and eliminate CTCs. The concurrent release of aPD-L1 at the tumour site could impair the PD-1/PD-L1 pathway and restore the tumour-killing effect of cytotoxic T cells. This chemoimmunotherapeutic strategy triggered relatively strong T cell immune responses, significantly improving the tumour immune microenvironment. CONCLUSION: Our findings indicated that the immunotherapeutic fibrin gel could "awaken" the host innate immune system to inhibit both local tumour recurrence post-surgery and metastatic potential, thus, it could serve as a promising approach to prevent tumour recurrence.

Nano-immunotherapy for each stage of cancer cellular immunity: which, why, and what?

Immunotherapy provides a new avenue for combating cancer. Current research in anticancer immunotherapy is primary based on T cell-mediated cellular immunity, which can be divided into seven steps and is named the cancer-immunity cycle. Unfortunately, clinical applications of cancer immunotherapies are restricted by inefficient drug delivery, low response rates, and unmanageable adverse reactions. In response to these challenges, the combination of nanotechnology and immunotherapy (nano-immunotherapy) has been extensively studied in recent years. Rational design of advanced nano-immunotherapies requires in-depth consideration of "which" immune step is targeted, "why" it needs to be further enhanced, and "what" nanotechnology can do for immunotherapy. However, the applications and effects of nanotechnology in the cancer-immunity cycle have not been well reviewed. Herein, we summarize the current developments in nano-immunotherapy for each stage of cancer cellular immunity, with special attention on the which, why and what. Furthermore, we summarize the advantages of nanotechnology for combination immunotherapy in two categories: enhanced efficacy and reduced toxicity. Finally, we discuss the challenges of nano-immunotherapy in detail and provide a perspective.

Research Note: Circular RNA expressing in different developmental stages of the chicken bursa of Fabricius.

The bursa of Fabricius plays an essential role in B lymphocyte development, which is controlled not only by proteins but by noncoding RNA. Circular RNA (circRNA) are expressed in diverse tissues in eukaryotes. To acquire a deeper perception of the molecular mechanism of bursal development, RNA sequencing was used to identify the circRNA during varied evolving stages of the chicken bursa of Fabricius. We identified 13,689 circRNA. All these circRNA were originated from 4565 chicken genes. Among them, only 1 circRNA was yielded from those 4131 parental genes, and 2 or more circular isoforms were generated from the remaining genes. There were 27 circRNA found to be differentially expressed between the embryonic day 20 and day 2 developmental stages. The 5 isoforms of immunoglobulin lambda-like polypeptide 1 circRNA were tested to validate the RNA sequencing data, and their targeted genes were also analyzed with quantitative reverse transcription PCR. These data indicate that cirRNA are abundant and essential during bursal development and may play essential roles in the development of bursa of Fabricius.