Enhancing ovarian cancer treatment with maleimide-modified Pt(IV) prodrug nanoparticles.

The limitations of platinum in ovarian cancer therapy, such as poor solubility and significant side effects, often lead to suboptimal therapeutic outcome and mortality. In this study, we have developed a novel approach utilizing biodegradable polymeric nanoparticles as a drug delivery system (NDDS), loaded with advanced platinum (IV) (Pt(IV)) prodrugs. A key feature of our approach is the enhancement of nanoparticles with maleimide, a modification hypothesized to significantly boost tumor tissue accumulation. When tested in mouse models of orthotopic and peritoneal metastasis ovarian cancer, these maleimide-modified nanoparticles are anticipated to show preferential accumulation in tumor tissues, enhancing therapeutic efficiency and minimizing systemic drug exposure. Our findings demonstrate that the maleimide-modified Pt(IV)-loaded NDDSs significantly reduce tumor burden in comparison to traditional cisplatin therapy, while simultaneously reducing adverse side effects. This leads to markedly improved survival rates in models of peritoneal metastasis ovarian cancer, offering a promising new direction in the treatment of this challenging disease.

Advancing mRNA Therapeutics: The Role and Future of Nanoparticle Delivery Systems.

The coronavirus (COVID-19) pandemic has underscored the critical role of mRNA-based vaccines as powerful, adaptable, readily manufacturable, and safe methodologies for prophylaxis. mRNA-based treatments are emerging as a hopeful avenue for a plethora of conditions, encompassing infectious diseases, cancer, autoimmune diseases, genetic diseases, and rare disorders. Nonetheless, the in vivo delivery of mRNA faces challenges due to its instability, suboptimal delivery, and potential for triggering undesired immune reactions. In this context, the development of effective drug delivery systems, particularly nanoparticles (NPs), is paramount. Tailored with biophysical and chemical properties and susceptible to surface customization, these NPs have demonstrated enhanced mRNA delivery in vivo and led to the approval of several NPs-based formulations for clinical use. Despite these advancements, the necessity for developing a refined, targeted NP delivery system remains imperative. This review comprehensively surveys the biological, translational, and clinical progress in NPs-mediated mRNA therapeutics for both the prevention and treatment of diverse diseases. By addressing critical factors for enhancing existing methodologies, it aims to inform the future development of precise and efficacious mRNA-based therapeutic interventions.

Harnessing nanomedicine for modulating microglial states in the central nervous system disorders: Challenges and opportunities.

Microglia are essential for maintaining homeostasis and responding to pathological events in the central nervous system (CNS). Their dynamic and multidimensional states in different environments are pivotal factors in various CNS disorders. However, therapeutic modulation of microglial states is challenging due to the intricate balance these cells maintain in the CNS environment and the blood-brain barrier's restriction of drug delivery. Nanomedicine presents a promising avenue for addressing these challenges, offering a method for the targeted and efficient modulation of microglial states. This review covers the challenges faced in microglial therapeutic modulation and potential use of nanoparticle-based drug delivery systems. We provide an in-depth examination of nanoparticle applications for modulating microglial states in a range of CNS disorders, encompassing neurodegenerative and autoimmune diseases, infections, traumatic injuries, stroke, tumors, chronic pain, and psychiatric conditions. This review highlights the recent advancements and future prospects in nanomedicine for microglial modulation, paving the way for future research and clinical applications of therapeutic interventions in CNS disorders.

Targeted delivery strategies: The interactions and applications of nanoparticles in liver diseases.

In recent years, nanoparticles have been broadly utilized in various drugs delivery formulations. Nanodelivery systems have shown promise in solving problems associated with the distribution of hydrophobic drugs and have promoted the accumulation of nanomedicines in the circulation or in organs. However, the injection dose of nanoparticles (NPs) is much greater than that needed by diseased tissues or organs. In other words, most of the NPs are localized off-target and do not reach the desired tissue or organs. With the rapid development of biodegradable and biosafety nanomaterials, the nanovectors represent assurance of safety. However, the off-target effects also induce concerns about the application of NPs, especially in the delivery of gene editing tools. Therefore, a complete understanding of the biological responses to NPs in the body will clearly guide the design of targeted delivery of NPs. The different properties of various nanodelivery systems may induce diverse interactions between carriers and organs. In this review, we describe the relationship between the liver, the most influenced organ of systemic administration of NPs, and targeted delivery nanoplatforms. Various transport vehicles have adopted multiple delivery strategies for the targeted delivery to the cells in the homeostasis liver and in diseased liver. Additionally, nanodelivery systems provide a novel strategy for treating incurable diseases. The appearance of a targeted delivery has profoundly improved the application of NPs to liver diseases.

Chemokine systems in oncology: From microenvironment modulation to nanocarrier innovations.

Over the past few decades, significant strides have been made in understanding the pivotal roles that chemokine networks play in tumor biology. These networks, comprising chemokines and their receptors, wield substantial influence over cancer immune regulation and therapeutic outcomes. As a result, targeting these chemokine systems has emerged as a promising avenue for cancer immunotherapy. However, therapies targeting chemokines face significant challenges in solid tumor treatment, due to the complex and fragile of the chemokine networks. A nuanced comprehension of the complicacy and functions of chemokine networks, and their impact on the tumor microenvironment, is essential for optimizing their therapeutic utility in oncology. This review elucidates the ways in which chemokine networks interact with cancer immunity and tumorigenesis. We particularly elaborate on recent innovations in manipulating these networks for cancer treatment. The review also highlights future challenges and explores potential biomaterial strategies for clinical applications.

Impacts of cationic lipid-DNA complexes on immune cells and hematopoietic cells in vivo.

The inability to systemic administration of nanoparticles, particularly cationic nanoparticles, has been a significant barrier to their clinical translation due to toxicity concerns. Understanding the in vivo behavior of cationic lipids is crucial, given their potential impact on critical biological components such as immune cells and hematopoietic stem cells (HSC). These cells are essential for maintaining the body's homeostasis, and their interaction with cationic lipids is a key factor in determining the safety and efficacy of these nanoparticles. In this study, we focused on the cytotoxic effects of cationic lipid/DNA complexes (CLN/DNA). Significantly, we observed that the most substantial cytotoxic effects, including a marked increase in numbers of long-term hematopoietic stem cells (LT-HSC), occurred 24 h post-CLN/DNA treatment in mice. Furthermore, we found that CLN/DNA-induced HSC expansion in bone marrow (BM) led to a notable decrease in the ability to reestablish blood cell production. Our study provides crucial insights into the interaction between cationic lipids and vital cellular components of the immune and hematopoietic systems.

Hit-and-run vaccine system that overcomes limited neoantigen epitopes for efficient broad antitumor response.

Neoantigen cancer vaccines have been envisioned as one of the most promising means for cancer therapies. However, identifying neoantigens for tumor types with low tumor mutation burdens continues to limit the effectiveness of neoantigen vaccines. Herein, we proposed a "hit-and-run" vaccine strategy which primes T cells to attack tumor cells decorated with exogenous "neo-antigens". This vaccine strategy utilizes a peptide nanovaccine to elicit antigen-specific T cell responses after tumor-specific decoration with a nanocarrier containing the same peptide antigens. We demonstrated that a poly(2-oxazoline)s (POx) conjugated with OVA257-264 peptide through a matrix metalloprotease 2 (MMP-2) sensitive linker could efficiently and selectively decorate tumor cells with OVA peptides in vivo. Then, a POx-based nanovaccine containing OVA257-264 peptides to elicit OVA-specific T cell responses was designed. In combination with this hit-and-run vaccine system, an effective vaccine therapy was demonstrated across tumor types even without OVA antigen expression. This approach provides a promising and uniform vaccine strategy against tumors with a low tumor mutation burden.

Cationic nanoparticles-based approaches for immune tolerance induction in vivo.

The development of autoimmune diseases and the rejection of transplanted organs are primarily caused by an exaggerated immune response to autoantigens or graft antigens. Achieving immune tolerance is crucial for the effective treatment of these conditions. However, traditional therapies often have limited therapeutic efficacy and can result in systemic toxic effects. The emergence of nanomedicine offers a promising avenue for addressing immune-related diseases. Among the various nanoparticle formulations, cationic nanoparticles have demonstrated significant potential in inducing immune tolerance. In this review, we provide an overview of the underlying mechanism of autoimmune disease and organ transplantation rejection. We then highlight the recent advancements and advantages of utilizing cationic nanoparticles for inducing immune tolerance in the treatment of autoimmune diseases and the prevention of transplant rejection.

Promoting the Recruitment, Engagement, and Reinvigoration of Effector T Cells via an Injectable Hydrogel with a Supramolecular Binding Capability for Cancer Immunotherapy.

T cells play a basic and key role in immunotherapy against solid tumors, and efficiently recruiting them into neoplastic foci and sustaining long-term effector function are consistent goals that remain a critical challenge. Here, an injectable alginate-based hydrogel with abundant ß-cyclodextrin (ALG-ßCD) sites is developed and intratumorally injected to recruit CCR9+ CD8+ T cells (a subset of T cells with robust antitumor activity) via the trapped chemokine CCL25. In the meantime, an intravenously injected adamantane-decorated anti-PD1 antibody (Ad-aPD1) would hitchhike on recruited CCR9+ CD8+ T cells to achieve the improved intratumoral accumulation of Ad-aPD1. Moreover, the Ad-PD1 and Ad-PDL1 antibodies are immobilized in the ALG-ßCD hydrogel through supramolecular host-guest interactions of Ad and ßCD, which facilitate engagement between CD8+ T cells and tumor cells and reinvigorate CD8+ T cells to avoid exhaustion. Based on this treatment strategy, T cell-mediated anticancer activity is promoted at multiple levels, eventually achieving superior antitumor efficacy in both orthotopic and postsurgical B16-F10 tumor models.

Advances in dendritic cell targeting nano-delivery systems for induction of immune tolerance.

Dendritic cells (DCs) are the major specialized antigen-presenting cells (APCs), play a key role in initiating the body's immune response, maintain the balance of immunity. DCs can also induce immune tolerance by rendering effector T cells absent and anergy, and promoting the expansion of regulatory T cells. Induction of tolerogenic DCs has been proved to be a promising strategy for the treatment of autoimmune diseases, organ transplantation, and allergic diseases by various laboratory researches and clinical trials. The development of nano-delivery systems has led to advances in situ modulation of the tolerance phenotype of DCs. By changing the material composition, particle size, zeta-potential, and surface modification of nanoparticles, nanoparticles can be used for the therapeutic payloads targeted delivery to DCs, endowing them with great potential in the induction of immune tolerance. This paper reviews how nano-delivery systems can be modulated for targeted delivery to DCs and induce immune tolerance and reviews their potential in the treatment of autoimmune diseases, organ transplantation, and allergic diseases.

In Vivo Immune Adjuvant Effects of CaCO3 Nanoparticles through Intracellular Ca2+ Concentration Regulation.

Calcium (Ca) is a vital component of the human body and plays a crucial role in intracellular signaling and regulation as a second messenger. Recent studies have shown that changes in intracellular Ca2+ concentration can influence immune cell function. In this study, we developed calcium carbonate nanoparticles (CaNPs) of various sizes using a Nanosystem Platform to modulate intracellular Ca2+ concentration in vitro and in vivo. Our findings demonstrate that intravenous administration of CaNPs led to changes in the number and ratio of immune cells in the spleen and stimulated the activation of dendritic cells (DCs) and macrophages. Notably, CaNPs exhibited strong adjuvant properties in the absence of antigenic stimuli. These results indicate that CaNPs have the potential to regulate immune cell function by modulating Ca2+ concentrations, offering a novel approach for disease prevention and treatment in combination with antigens or drugs. Overall, our study emphasizes the importance of modulating intracellular Ca2+ concentration as a means of regulating immune cell function.

Co-delivery of vitamin D3 and Lkb1 siRNA by cationic lipid-assisted PEG-PLGA nanoparticles to effectively remodel the immune system in vivo.

The imbalance of the immune system can lead to the occurrence of autoimmune diseases. Controlling and regulating the proliferation and function of effector T (Teff) cells and regulatory T (Treg) cells becomes the key to treating these diseases. Dendritic cells (DCs), as dedicated antigen-presenting cells, play a key role in inducing the differentiation of naive CD4+ T cells. In this study, we designed a cationic lipid-assisted PEG-PLGA nanoparticle (NPs/VD3/siLkb1) to deliver 1,25-dihydroxyvitamin D3 (VD3) and small interfering RNA (siRNA) to DC cells in the draining lymph nodes. By modulating the phenotypic changes of DC cells, this approach expands Treg cells and reduces the occurrence of autoimmune diseases. Thus, this study provides a novel approach to alleviating the occurrence and development of autoimmune diseases while also minimizing the risk of unwanted complications.

Maleimide as the PEG end-group promotes macrophage-targeted drug delivery of PEGylated nanoparticles in vivo by enhancing interaction with circulating erythrocytes.

Radiotherapy (IR) is capable of enhancing antitumor immune responses. However, IR treatment also aggravates the infiltration of peripheral macrophages into the tumor, resulting in reversing the therapeutic effects of antitumor immunity. Thus, a strategy to effectively prevent tumor infiltration by macrophages may further improved the therapeutic efficacy of radiotherapy. Herein, we found that PEGylated solid lipid nanoparticles with maleimide as PEG end-group (SLN-PEG-Mal) show significantly enhanced adsorption onto RBCs through reacting with reactive sulfhydryl groups on RBCs' surface both in vitro and in vivo, and caused significant changes in the surface properties and morphology of RBCs. These RBCs adsorbed by SLN-PEG-Mal were rapidly removed from circulation due to efficient engulfment by reticuloendothelial macrophages, supporting the usefulness of SLN-PEG-Mal for macrophage-targeted drug delivery. While lacking the use of radioisotope tracing (considered the gold standard for PK/BD studies), our data align with the expected pathway of host defense activation through surface-loaded RBCs. Importantly, injection of paclitaxel-loaded SLN-PEG-Mal effectively inhibited the tumor-infiltration by macrophages, and significantly improved the antitumor immune responses in tumor-bearing mice treated with low-dose irradiation. This study provides insights into the effects of maleimide as PEG end-group on enhancing the interaction between PEGylated nanoparticles and RBCs and offers an effective strategy to inhibit tumor infiltration by circulating macrophages.

The altered expression of cytoskeletal and synaptic remodeling proteins during epilepsy.

The cytoskeleton plays an important role in epilepsy; however, the mechanism is unknown. Therefore, this study aimed to reveal the mechanism of cytoskeletal proteins in epilepsy by investigating the expression of cytoskeletal proteins and synaptophysin (SYP) in mice at 0, 3, 6, and 24 h, 3 days, and 7 days in a kainic acid (KA)-induced epileptic model. Our results demonstrated that the expression of F-actin decreased significantly between 3 and 6 h, 6 and 24 h, and 24 h and 3 days (P < 0.05). Meanwhile, the expression of the neurofilament light chain, neurofilament medium chain, and neurofilament heavy chain subunits was significantly decreased (P < 0.001) at 3 h after the KA injection compared to the KA 0 h group, followed by an elevation at 6 h and a further decrease at 24 h compared to at 6 h. SYP expression was significantly decreased between 0 and 3 h as well as between 3 and 6 h (P < 0.05). At 24 h, the level was increased compared to at 6 h and continued to increase at 3 days after the KA injection. Thus, we propose that cytoskeletal proteins may be involved in the pathogenesis of epilepsy.

Biosafety risk assessment of gold and aluminum nanoparticles in tumor-bearing mice.

To improve the biosafety of the nanodelivery system, this study developed novel monodisperse spherical aluminum nanoparticles (Al NPs) and evaluated their cytotoxicity in vitro and distribution and biotoxicity in vivo. Compared with gold nanoparticles of the same size, Al NPs not only had low cytotoxicity in vitro but also did not cause accumulation in major organs in vivo after intravenous injections. No significant abnormalities were observed in the serum biochemical indices of mice injected with Al NPs. Additionally, no substantial changes occurred in the histopathology of major organs, and no apparent biological toxicity was measured after consecutive injections of Al NPs. These results indicate that Al NPs have a good biological safety and provide a new method for developing low-toxicity nanomedicine.

Nanoparticle delivery of CD40 siRNA suppresses alloimmune responses by inhibiting activation and differentiation of DCs and macrophages.

CD40 is an important costimulatory molecule expressed on antigen-presenting cells (APCs) and plays a critical role for APC activation, offering a promising therapeutic target for preventing allograft rejection. Here, we developed a biodegradable nanoparticle small interfering RNA delivery system (siCD40/NPs) to effectively deliver CD40 siRNA (siCD40) into hematopoietic stem cells (HSCs), myeloid progenitors, and mature dendritic cells (DCs) and macrophages. Injection of siCD40/NPs not only down-regulated CD40 expression in DCs and macrophages but also inhibited the differentiation of HSCs and/or myeloid progenitors into functional DCs and macrophages. Furthermore, siCD40/NPs treatment significantly prolonged allograft survival in mouse models of skin allotransplantation. In addition to reiteration of the role of CD40 in APC activation, our findings highlight a previously unappreciated role of CD40 in DC and macrophage differentiation from their progenitors. Furthermore, our results support the effectiveness of siCD40/NPs in suppressing alloimmune responses, providing a potential means of facilitating tolerance induction and preventing allotransplant rejection.

Vibratome sectioning of tumors to evaluate the interactions between nanoparticles and the tumor microenvironment ex-vivo.

Nanoparticles have been investigated as drug carriers and promising agents for cancer therapy. However, the tumor microenvironment (TME), which is formed by the tumor, is considered a barrier for nanocarriers to enter the internal tumor tissue. Therefore, the evaluation of the biological distribution of nanocarriers in TME can provide useful information on their role in tumor-targeted drug delivery. Although the tumor-bearing mouse model is commonly used to investigate the distribution of nanocarriers in the TME, there is currently a lack of a testing system to predict the distribution of nanocarriers in tumor tissues, especially in patients. This study revealed that the macrophages and dendritic cells (DCs) were more distributed in the peripheral part than the central part of the tumor, which might be an obstacle to the uniform distribution of nanoparticles in the tumor. In addition, the cellular uptake of gold nanoparticles (AuNR and AuNS) in macrophages and DCs cell lines (RAW264.7 and DC1.2) was markedly different from that in the TME. Hence, the study model of the interaction between nanoparticles and macrophages and DCs has an important impact on the accuracy of the results. The vibratome sections of tumor tissues preserved the spatial distribution of immune cells and tumor cells, and had very little effects on their morphologies and activities. More importantly, we found that the distribution of nanocarriers in vibratome sections was similar to that in tumors in vivo. In all, ex vivo analysis using vibratome sections of tumor tissues provides a more convenient and stable method for elucidating the influences of TME on the distribution of nanocarriers.

Lipid-mediated delivery of CD47 siRNA aids JQ1 in ensuring simultaneous downregulation of PD-L1 and CD47 and improves antitumor immunotherapy efficacy.

Cancer immunotherapy using immune checkpoint blockade has become an attractive treatment option for patients with different cancers. JQ1, an indirect inhibitor of MYC, enhances antitumor immune responses by regulating the expression of programmed death-ligand 1 (PD-L1) and cluster of differentiation 47 (CD47) in tumor cells; however, its role in downregulating the expression of CD47 remains elusive. The present study revealed that JQ1 failed to downregulate and, when used at high concentrations, it unexpectedly upregulated the expression of CD47 in murine B16F10 melanoma and 4T1 breast tumor cells. Hence, the combinatory use of JQ1 and CD47-specific short interfering RNA (siRNA) may lead to an improved antitumor effect. To overcome the poor water solubility of JQ1 and enhance tumor-targeted delivery, cationic lipid nanoparticles (CLNs) encapsulating both JQ1 and siCD47 simultaneously (CLN/JQ1/siCD47) or each individually (CLN/JQ1/siNC or CLN/siCD47) were prepared. CLN/JQ1/siCD47, but not CLN/JQ1/siNC or CLN/siCD47, simultaneously downregulated both PD-L1 and CD47 in vitro and in vivo. Furthermore, compared with CLN/JQ1/siNC and CLN/siCD47, CLN/JQ1/siCD47 induced a significantly enhanced antitumor effect in mice with established breast cancer. The results of this study highlight a synergistic effect of simultaneous PD-L1 and CD47 downregulation and provide a novel strategy for improving the antitumor effects of JQ1.

An optimized ionizable cationic lipid for brain tumor-targeted siRNA delivery and glioblastoma immunotherapy.

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with a high mortality rate. Immunotherapy has achieved promising clinical results in multiple cancers, but shows unsatisfactory outcome in GBM patients, and poor drug delivery across the blood-brain barrier (BBB) is believed to be one of the main limitations that hinder the therapeutic efficacy of drugs. Herein, a new cationic lipid nanoparticle (LNP) that can efficiently deliver siRNA across BBB and target mouse brain is prepared for modulating the tumor microenvironment for GBM immunotherapy. By designing and screening cationic LNPs with different ionizable amine headgroups, a lipid (named as BAMPA-O16B) is identified with an optimal acid dissociation constant (pKa) that significantly enhances the cellular uptake and endosomal escape of siRNA lipoplex in mouse GBM cells. Importantly, BAMPA-O16B/siRNA lipoplex is highly effective to deliver siRNA against CD47 and PD-L1 across the BBB into cranial GBM in mice, and downregulate target gene expression in the tumor, resulting in synergistically activating a T cell-dependent antitumor immunity in orthotopic GBM. Collectively, this study offers an effective strategy for brain targeted siRNA delivery and gene silencing by optimizing the physicochemical property of LNPs. The effectiveness of modulating immune environment of GBM could further be expanded for potential treatment of other brain tumors.

Kidney functional stages influence the role of PEG end-group on the renal accumulation and distribution of PEGylated nanoparticles.

Modification with polyethylene glycol (PEG), or PEGylation, has become a popular method to improve the efficiency of drug delivery in vivo using nanoparticle-based delivery systems. The PEG end-group plays an important role in the in vivo fate of PEGylated nanoparticles through its interactions with proteins in the serum and the cell membrane. However, the effects of PEG end-groups on the renal clearance of PEGylated nanoparticles remain unclear. Kidney function may also affect the renal accumulation and distribution of nanoparticles. Herein, we demonstrate that the accumulation and distribution of PEGylated nanoparticles in kidneys are significantly affected by both the PEG end-group and kidney function damage. Interestingly, compared to PEG with an amino or methoxy end-group, PEG with maleimide as the end-group markedly enhanced the accumulation of PEGylated nanoparticles in normal kidneys, which may improve renal clearance. However, obvious enhancements in the renal accumulation and medullary distribution of PEGylated nanoparticles are detected in kidneys with functional impairment. Damage to renal function further affects how the PEG end-group influences the accumulation and distribution of PEGylated nanoparticles in kidneys in vivo. Collectively, the findings provide deep insights into the interactions between PEGylated nanoparticles and kidneys in vivo.