Search

Idiopathic pulmonary fibrosis (IPF) is a fibrotic interstitial lung disease in which collagen progressively deposits in the supporting framework of the lungs. The pathological collagen creates a recalcitrant barrier in mesenchyme for drug penetration, thus greatly restricting the therapeutical efficacy. On the other hand, this overloaded collagen is gradually exposed to the bloodstream at fibrotic sites because of the vascular hyperpermeability, thus serving as a potential target. Herein, pathological collagen targeting and penetrating liposomes (DP-CC) were constructed to deliver anti-fibrotic dual drugs including pirfenidone (PFD) and dexamethasone (DEX) deep into injured alveoli. The liposomes were co-decorated with collagen binding peptide (CBP) and collagenase (COL). CBP could help vehicle recognize the pathological collagen and target the fibrotic lungs efficiently because of its high affinity to collagen, and COL assisted in breaking through the collagen barrier and delivering vehicle to the center of injured sites. Then, the released dual drugs developed a synergistic anti-fibrotic effect to repair the damaged epithelium and remodel the extracellular matrix (ECM), thus rebuilding the lung architecture. This study provides a promising strategy to deliver drugs deep into pathological collagen accumulated sites for the enhanced treatment of IPF.

Triple-negative breast cancer constitutes 15 – 20% of all breast cancer and is considered one of the most aggressive forms of breast cancer. Clinical studies have suggested that the high numbers of infiltrating tumor-associated macrophage (TAM) act as a critical contributor behind the aggression of TNBC. Therefore, this study was focused on the preparation of a TNBC spheroid model with M2-like macrophages (M2-M) since it closely simulated the tumor microenvironment observed in clinical TNBC tumors. High EGFR expression in TNBC highlights the importance of cetuximab (Cmab)-assisted cellular internalization into the EGFR overexpressing TNBC cell line. The Cmab-anchored gold nanorod (GNR)-mediated photothermal approach was successfully developed to treat the TAM-infiltrated TNBC spheroid model. MDA-MB-231 spheroids with a diameter of 260 ± 10 μm were successfully prepared. An increase in the IC50 of doxorubicin in MDA-MB-231 spheroids with M2-M compared to the without M2-M group suggested that TAM-mediated development of resistance. The in vitro cytotoxicity assay demonstrated that there was elevated apoptosis expression (PARP and caspase-9), cell cycle arrest (G2/M phase), and cytotoxic effects following treatment with Cmab-GNR plus NIR irradiation. Moreover, there was no significant difference between the cytotoxic effect of Cmab-GNR plus NIR with M2-M and without M2-M group. Thus, our study highlighted that Cmab-GNR with NIR were able to overcome TAM-acquired resistance in the tumor model, which might be due to the polarization of the protumoral phenotype to the antitumoral phenotype.

Chemo-resistance has pushed cancer treatment to the boundary of failure. This challenge has encouraged scientists to look for nanotechnological solutions. In this study, we have taken this goal one step further without depending on chemotherapy. Specifically, hybrid metal, polymer, and lipid nanoparticles that formed an IR780-a photosensitizer and Zinc copper oxide incorporated nanoparticle (ZCNP) nanoparticles were utilized in a combined photothermal and photodynamic therapy. Through the mediation of triphenylphosphonium (TPP) as a mitochondria-targeting moiety, TPP-conjugated polymer-lipid hybrid nanoparticles containing ZCNP/IR-780 significantly enhanced cellular uptake by cancer cells and selectively targeted the mitochondria, which improved the induction of apoptosis. In tumor-bearing mice, the nanoparticles were detected predominantly in tumors rather than in the other principle organs, which did not show notable signs of toxicity. Both in vitro and in vivo results demonstrated a great improvement in photothermal and photodynamic efficacy in combination when compared to either one individually, and a significant inhibition of tumor growth was observed with the combined therapies. In summary, this study describes an effective mitochondria-targeting nanocarrier for the treatment of cancer using combined photothermal and photodynamic therapies.

Immunomodulation is an essential consideration for cell replacement procedures. Unfortunately, lifelong exposure to nonspecific systemic immunosuppression results in immunodeficiency and has toxic effects on nonimmune cells. Here, we engineered hybrid spheroids of mesenchymal stem cells (MSCs) with rapamycin-releasing poly(lactic- co -glycolic acid) microparticles (RAP-MPs) to prevent immune rejection of islet xenografts in diabetic C57BL/6 mice. Hybrid spheroids were rapidly formed by incubating cell-particle mixture in methylcellulose solution while maintaining high cell viability. RAP-MPs were uniformly distributed in hybrid spheroids and sustainably released RAP for ~3 weeks. Locoregional transplantation of hybrid spheroids containing low doses of RAP-MPs (200- to 4000-ng RAP per recipient) significantly prolonged islet survival times and promoted the generation of regional regulatory T cells. Enhanced programmed death-ligand 1 expression by MSCs was found to be responsible for the immunomodulatory performance of hybrid spheroids. Our results suggest that these hybrid spheroids offer a promising platform for the efficient use of MSCs in the transplantation field.

Amalgamation of the reactive oxygen species (ROS)-responsive stimulus with nanoparticles has gained considerable interest owing to their high tumor specificity. Hypoxia plays a pivotal role in the acceleration of intracellular ROS production. Herein, we report the construction of a cancer cell (PD-L1)- and ROS-responsive, dual-targeted, temozolomide (TMZ)-laden nanosystem which offers a better anticancer effect in a hypoxic tumor microenvironment. A dual-targeted system boosted permeation in the cancer cells. Hypoxic conditions elevating the high ROS level accelerated the in situ release of TMZ from anti-PD-L1-TKNPs. Hyperaccumulated ROS engendered from TMZ caused oxidative damage leading to mitochondria-mediated apoptosis. TMZ fabricated in the multifunctional nanosystem (anti-PD-L1-TMZ-TKNPs) provided excellent tumor accumulation and retarded tumor growth under in vivo conditions. The elevated apoptosis effect with the activation of an apoptotic marker, DNA double-strand breakage marker, and downregulation of the angiogenesis marker in the tumor tissue following treatment with anti-PD-L1-TMZ-TKNPs exerts robust anticancer effect. Collectively, the nanoconstruct offers deep tumor permeation and high drug release and broadens the application of the ROS-responsive nanosystem for a successful anticancer effect.

Parkinson’s disease (PD) is the most common progressive neurodegenerative disorder and is characterized by the degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNC). To date, none of the strategies, such as pharmacological, non-pharmacological, and neurosurgical therapies, have been capable of fundamental treatment of PD. These types of treatments provide only symptomatic relief, and effective targeting for PD has lagged behind other disease areas, due to drug delivery challenges caused by the blood–brain barrier (BBB). This review focus on the immunologic and nanoformulation strategies used for the treatment of PD. In this review, we discuss the current strategies that offer the development of immunotherapies, antibody-based therapies, and nanoparticles (NPs)-based therapy to reduce the burden of degeneration of DA neurons due to synucleinopathies and elevation of proinflammatory cytokines in the central nervous system (CNS). Furthermore, this review presents current ongoing clinical trials. The accumulation and transmission of α-synuclein and activation of glial cells cause the death of dopaminergic neurons and lead to the progression of PD. Many studies have investigated the immunotherapies and NPs-based therapy that target α-synuclein, and microglia, which have been shown to effectively prevent the progression of α-synuclein deposition and microglia deactivation. Furthermore, at present, the formulations of different drugs, such as DA, levodopa (L-DOPA), monoamine oxidase inhibitors (MAO-I), and antioxidants, is administered with a multifunctional carrier that can penetrate the BBB. Therefore, rapid clinical progression on these strategies gives new hope in the therapy of PD.

Ovarian cancer is the most significant cause of gynecological cancer mortality, with the majority of women with advanced disease. Although surgery and chemotherapy can enhance survival rates, the 5-year survival rates remain low at 45%. So, alternative treatment options need to be implemented to improve therapeutic outcomes. In the ovarian cancer tumor, the presence of T cells helps to improve the progression-free and overall survival, whereas a poor prognosis corresponds to the presence of regulatory T cells and expression of T cells inhibitory molecules. Analyzing the important role of these immune systems in cancer management, immunotherapy may create a sustained response to recurring ovarian cancer cells in the immune system. In addition, by boosting anti-tumor immune response, women’s prognosis with this lethal disease can be significantly influenced. Different immunotherapeutic strategies and nanoparticle-based strategies were used as potential treatment options to challenge tumor progression. This review discusses cytokine therapy, peptide vaccine, monoclonal antibody, dendritic cell-based vaccine, adoptive T cells transfer, and immune checkpoint inhibitors as well as different nanoparticles such as poly (lactic-co-glycolic) acid nanoparticles, polyethyleneimine-based nanoparticles, and liposomes that offer a new paradigm in the treatment of ovarian cancer.

Islet cell transplantation has been an effective method for the treatment of type 1 diabetes. The transplanted islets release insulin in response to changes in blood glucose levels. The clinical application of islet transplantation, however, has been hindered because of some critical problems including immune responses to grafted islets and side effects caused by overdosed immunosuppressive drugs. Herein, surface modification technology using poly(ethylene glycol) (PEG)-dendron was proposed to safeguard islets from the host immune system. PEG-dendron was synthesized by a divergent polymerization method and utilized to cover the islet antigen surface. Successful conjugation of PEG-dendron on the islet surface was achieved without affecting islet morphology, viability, and functionality at a concentration of 1.00%. Surface modification using PEG-dendron effectively prevented protein absorption and immune activation. Foremost, it improved the survival rate of islet grafts in vivo when combined with a low dose of immunosuppressive drugs. In conclusion, PEG-dendron is a potential candidate for the surface modification of pancreatic islets to mitigate immune responses after transplantation.

Accumulating clinical data shows that less than half of patients are beneficial from PD-1/PD-L1 blockage therapy owing to the limited infiltration of effector immune cells into the tumor and abundant of the immunosuppressive factors in the tumor microenvironment. In this study, PD-L1 inhibition therapy and BRAF-targeted therapy, which showed clinical benefit, were combined in a CXCR4-targeted nanoparticle co-delivering dabrafenib (Dab), a BRAF inhibitor, and miR-200c which can down-regulate PD-L1 expression. The cationic PCL-PEI core containing Dab- and miR-200c- were coated with poly-L-glutamic acid conjugated with LY2510924, a CXCR-4 antagonist peptide, (PGA-pep) to obtain miR@PCL-PEI/Dab@PGA-pep nanoformulation. The stimulus pH- and redox- reactive of PGA-pep was ascribed to exhibit an enhanced release of drug in the tumor microenvironment as well as improve the stability of miR-200c during the blood circulation. In addition, the presence of LY2510924 peptide would enhance the binding affinity of miR@PCL-PEI/Dab@PGA-pep NPs to cancer cells, leading to improved cellular uptake, cytotoxicity, and in vivo accumulation into tumor area. The in vivo results indicated that both, the immunogenic cell death (ICD) and the inhibition of PD-L1 expression, induced by treatment with CXCR-4 targeted nanoparticles, enables to improve the DC maturation in lymph node and CD8+ T cell activation in the spleen. More importantly, effector T cells were increasingly infiltrated into the tumor, whereas the immunosuppressive factors like PD-L1 expression and regulatory T cells were significantly reduced. They, all together, promote the immune responses against the tumor, indicating the therapeutic efficiency of the current strategy in cancer treatment.

Targeted and stimuli-sensitive nanobombs for the release of therapeutic agents after laser irradiation of the tumor site are gaining widespread attention as personalized anticancer regimens. In this study, redox and photo dual-responsive, folate receptor-targeted nanourchin carriers for chemo-, photodynamic, and photothermal therapy were constructed by the amalgamation of an outer layer of polyethylene glycol (PEG)-S-S-methotrexate (MTX) and an inner core of indocyanine green (ICG)-loaded bismuth sulfide (Bi2S3) nanoparticles for cancer treatment. MTX introduces the carrier to folate receptors resulting in the internalization of nanoparticles into cancer cells, specifically and increasingly. In the reducing environment inside cancer cells, MTX was cleaved, resulting in a burst release that effectively inhibited tumor growth. Simultaneously, the fusion of Bi2S3 and ICG in the inner core absorbed energy from a near-infrared radiation (NIR) laser to generate heat and reactive oxygen species, which further ablated the tumors and synergistically enhanced the anticancer activity of MTX. These results indicate the successful preparation of combined nanourchins (NUs) showing GSH-induced and laser-responsive release of MTX and ICG, accompanied by hyperthermia via Bi2S3 and ICG. Effective in vitro cellular internalization, cellular cytotoxicity, and pro-apoptotic behavior of the nanosystem were achieved through a targeting, redox, and NIR-responsive combination strategy. In vivo biodistribution and photothermal imaging also revealed tumor-selective and -retentive, as well as thermally responsive attributes. Ultimately, this in vivo antitumor study shows an effective tumor ablation by these nanourchins without affecting the vital organs. Our findings indicate that using these targeted redox- and laser-responsive combination therapeutic carriers can be a promising strategy in folate receptor-expressing tumors.

The consolidation of nanovectors with biological membranes has recently been a subject of interest owing to the prolonged systemic circulation time and delayed clearance by the reticuloendothelial system of such systems. Among the different biomembranes, the macrophage membrane has a similar systemic circulation time, with an additional chemotactic aptitude, targeting integrin proteins. In this study, we aimed to establish a laser-activated, disintegrable, and deeply tumor-penetrative nanoplatform. We used a highly tumor-ablative and laser-responsive disintegrable copper sulfide nanoparticle, loaded it with paclitaxel, and camouflaged it with the macrophage membrane for the fabrication of PTX@CuS@MMNPs. The in vitro paclitaxel release profile was favorable for release in the tumor microenvironment, and the release was accelerated after laser exposure. Cellular internalization was improved by membrane encapsulation. Cellular uptake, cytotoxicity, reactive oxygen species generation, and apoptosis induction of PTX@CuS@MMNPs were further improved upon laser exposure, and boosted permeation was achieved by co-administration of the tumor-penetrating peptide iRGD. In vivo tumor accumulation, tumor inhibition rate, and apoptotic marker expression induced by PTX@CuS@MMNPs were significantly improved by laser irradiation and iRGD co-administration. PTX@CuS@MMNPs induced downregulation of cellular proliferation and angiogenic markers but no significant changes in body weight, survival, or significant toxicities in vital organs after laser exposure, suggesting their biocompatibility. The disintegrability of the nanosystem, accredited to biodegradability, favored efficient elimination from the body. In conclusion, PTX@CuS@MMNPs showed promising traits in combination therapies for excellent tumor eradication.

Mesenchymal stromal cells (MSCs) have received attention as promising therapeutic agents for the treatment of various diseases. However, poor post-transplantation viability is a major hurdle in MSC-based therapy, despite encouraging results in many inflammatory disorders. Recently, three dimensional (3D)-cultured MSCs (MSC3D) were shown to have higher cell survival and enhanced anti-inflammatory effects, although the underlying mechanisms have not yet been elucidated. In this study, we investigated the molecular mechanisms by which MSC3D gain the potential for enhanced cell viability. Herein, we found that macroautophagy/autophagy was highly induced and ROS production was suppressed in MSC3D as compared to 2D-cultured MSCs (MSC2D). Interestingly, inhibition of autophagy induction caused decreased cell viability and increased apoptotic activity in MSC3D. Furthermore, modulation of ROS production was closely related to the survival and apoptosis of MSC3D. We also observed that HMOX1 (heme oxygenase 1) was significantly up-regulated in MSC3D. In addition, gene silencing of HMOX1 caused upregulation of ROS production and suppression of the genes related to autophagy. Moreover, inhibition of HIF1A (hypoxia inducible factor 1 subunit alpha) caused suppression of HMOX1 expression in MSC3D, indicating that the HIF1A-HMOX1 axis plays a crucial role in the modulation of ROS production and autophagy induction in MSC3D. Finally, the critical role of autophagy induction on improved therapeutic effects of MSC3D was further verified in dextran sulfate sodium (DSS)-induced murine colitis. Taken together, these results indicated that autophagy activation and modulation of ROS production mediated via the HIF1A-HMOX1 axis play pivotal roles in enhancing the viability of MSC3D.Abbreviations: 3D: three dimensional; 3MA: 3 methlyadenine; AMPK: AMP-activated protein kinase; Baf A1: bafilomycin A1; CFSE: carboxyfluorescein succinimidyl ester; CoCl2: cobalt chloride; CoPP: cobalt protoporphyrin; DSS: dextran sulfate sodium; ECM: extracellular matrix; FOXO3/FOXO3A: forkhead box O3; HIF1A: hypoxia inducible factor 1 subunit alpha; HMOX1/HO-1: heme oxygenase 1; HSCs: hematopoietic stem cells; IL1A/IL-1α: interleukin 1 alpha; IL1B/IL-1β: interleukin 1 beta; IL8: interleukin 8; KEAP1: kelch like ECH associated protein 1; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; MSC2D: 2D-cultured MSCs; MSC3D: 3D-cultured MSCs; MSCs: mesenchymal stromal cells; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; PGE2: prostaglandin E2; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PINK1: PTEN induced kinase 1; ROS: reactive oxygen species; siRNA: small interfering RNA; SIRT1: sirtuin 1; SOD2: superoxide dismutase 2; SQSTM1/p62: sequestosome 1; TGFB/TGF-β: transforming growth factor beta.

Cancer stem cells (CSCs) are the subpopulation of cells present within a tumor with the properties of self-renewing, differentiating, and proliferating. Owing to the presence of ATP-binding cassette drug pumps and increased expression of anti-apoptotic proteins, the conventional chemotherapeutic agents have failed to eliminate CSCs resulting in relapse and resistance of cancer. Therefore, to obtain long-lasting clinical responses and avoid the recurrence of cancer, it is crucial to develop an efficient strategy targeting CSCs by either employing a differentiation therapy or specifically delivering drugs to CSCs. Several intracellular and extracellular cancer specific biomarkers are overexpressed by CSCs and are utilized as targets for the development of new approaches in the diagnosis and treatment of CSCs. Moreover, several nanostructured particles, alone or in combination with current treatment approaches, have been used to improve the detection, imaging, and targeting of CSCs, thus addressing the limitations of cancer therapies. Targeting CSC surface markers, stemness-related signaling pathways, and tumor microenvironmental signals has improved the detection and eradication of CSCs and, therefore, tumor diagnosis and treatment. This review summarizes a variety of promising nanoparticles targeting the surface biomarkers of CSCs for the detection and eradication of tumor-initiating stem cells, used in combination with other treatment regimens.

Based on the severity of the disease progression, the treatment of ulcerative colitis involves administration of single or multiple therapeutic agents. In refractory cases of ulcerative colitis, FK506 (FK) is the drug of choice in clinics. To maintain a long-term stable blood concentration of FK and to reduce its dosing frequency, we propose single-dose injection of FK-loaded biodegradable microspheres (FK-Ms). FK-Ms were intraperitoneally-injected into mice fed with dextran-sulfate sodium (DSS). Pharmacokinetics study revealed presence of FK in blood for over 20 days. The single intraperitoneal injection of the drug-loaded microspheres effectively alleviated DSS-induced murine colitis. Mechanistically, the single injection of FK-Ms inhibited the infiltration of T cells into colon and attenuated differentiation of T cells into interferon-γ secreting Th1 and interleukin-17A secreting Th17 cells in colon-draining mesenteric lymph nodes. Therefore, administration of prolonged-release type microspheres can be considered as an alternative for the effective treatment of inflammatory bowel diseases.

The mechanism of cell death has attracted a great deal of research interest in the design of antitumor therapy in recent days. Several attempts have been carried out in this direction and in our study also, we studied this phenomenon with the design of panitumumab (PmAb)-conjugated and temozolomide (TMZ)-loaded poly(lactic-co-glycolic acid) nanoparticles (PLGA-NPs), termed PmAb-TMZ-PLGA-NPs. First, PmAb was functionalized on the surface of TMZ-PLGA-NPs using ethyl(dimethylaminopropyl)carbodiimide (EDC)-N-hydroxysuccinimide (NHS) chemistry. Targeted PLGA-NPs significantly enhanced the cellular uptake of nanoparticles in the U-87 MG cell line as a result of the high epidermal growth factor receptor (EGFR) expression, compared to the LN229 cell line. Our study demonstrated that following the treatment of PmAb-TMZ-PLGA-NPs, a more pronounced anticancer effect was noticed in comparison with free TMZ and TMZ-PLGA-NPs. Further, a more pronounced cytotoxic effect of PmAb-TMZ-PLGA-NPs was observed in the high EGFR-overexpressed glioblastoma multiforme (GBM) model (U-87 MG) cell line compared to the low EGFR GBM model (LN229). Our study demonstrated that the treatment of PmAb-TMZ-PLGA-NPs in GBM tried to adopt the autophagic pathway of the cell survival mechanism with the elevated level of autophagic marker (Beclin-1 and LC3B) at 24 h time point, thereby suppressing the expression of caspase-9 and PARP. However, at the 48 h time point, the elevated expression of caspase-9 and PARP with the downregulation of Beclin-1 and LC3B, following the treatment of PmAb-TMZ-PLGA-NPs in the GBM model, suggested that apoptotic cell death was superior over autophagic cell survival. It was also noteworthy the activation of caspase-9 was correlated with the continuous overproduction of reactive oxygen species up to a 48 h time point after the treatment of PmAb-TMZ-PLGA-NPs. This result sheds light on the biological effect of targeted chemotherapy and illustrates that PmAb-TMZ-PLGA-NPs could be applied for EGFR-overexpressed different cancer models.

The therapeutic efficacy of current cancer vaccines is far from optimal, mainly because of insufficient induction of antigen-specific T cells and because tumor cells can hijack immunosuppressive mechanisms to evade the immune responses. Generating specific, robust, and long-term immune responses against cancer cells and the attenuating of immunosuppressive factors are critical for effective cancer vaccination. Recently, the engineering of exosomes specifically bind to T cells, and then stimulating tumor-specific T-cell immune responses has emerged as a potential alternative strategy for cancer vaccination. In this study, we generated a bifunctional exosome combining the strategy of vaccination and checkpoint blockade. Exosomes prepared from Ovalbumin (OVA)-pulsed, activated dendritic cells were modified with anti-CTLA-4 antibody (EXO-OVA-mAb) to block this inhibitory molecule and to enhance the specificity of the exosomes toward T cells. Our study provides a unique strategy for functionalizing exosome membrane with anti-CTLA-4 antibody via lipid-anchoring method to synergize efficacy of cancer vaccination and immune checkpoint blockade against the tumor. Statement of Significance We designed T-cell-targeting exosomes (EXO-OVA-mAb) decorated with costimulatory molecules, MHCs, antigenic OVA peptide, and anti-CTLA-4 antibody, combining the strategies of vaccines and checkpoint blockade. The exosomes showed enhanced binding to T cells in tumor-draining lymph nodes, effectively induced T-cell activation, and improved the tumor homing of effector T cells, ultimately significantly restraining tumor growth. Thus, EXO-OVA-mAb greatly facilitates T-cell targeting, induces a strong tumor-specific T-cell response, and increased the ratio of effector T cells/regulatory T cells within tumors, resulting in appreciable tumor growth inhibition.

Cancer immunotherapy evolved as a new treatment modality to eradicate tumor cells and has gained in popularity after its successful clinical transition. By activating antigen-presenting cells (APCs), and thus, inducing innate or adaptive immune responses, immunoadjuvants have become promising tools for cancer immunotherapy. Different types of immunoadjuvants such as toll-like receptor (TLR) agonists, exosomes, and metallic and plant-derived immunoadjuvants have been studied for their immunological effects. However, the clinical use of immunoadjuvants is limited by short response rates and various side-effects. The rapid progress made in the development of nanoparticle systems as immunoadjuvant carrier vehicles has provided potential carriers for cancer immunotherapy. In this review article, we describe different types of immunoadjuvants, their limitations, modes of action, and the reasons for their clinical adoption. In addition, we review recent progress made in the nanoparticle-based immunoadjuvant field and on the combined use of nanoparticle-based immunoadjuvants and chemotherapy, phototherapy, radiation therapy, and immune checkpoint inhibitor-based therapy. Statement of Significance Cancer immunotherapy emerged as a new hope for treating malignant tumors. Different types of immunoadjuvants serve as an important tool for cancer immunotherapy by activating an innate or adaptive immune response. Limitation of free immunoadjuvant has paved the path for the development of nanoparticle-based immunoadjuvant therapy with the hope of prolonging the therapeutic efficacy. This review highlights the recent advancement made in nanoparticle-based immunoadjuvant therapy in modulating the adaptive and innate immune system. The application of the combinatorial approach of chemotherapy, phototherapy, radiation therapy adds synergy in nanoparticle-based immunoadjuvant therapy. It will broaden the reader's understanding on the recent progress made in immunotherapy with the aid of immunoadjuvant-based nanosystem.

Enteric-coated formulations using Eudragit® polymers have been extensively used for delivering drugs to the lower gastrointestinal tract. However, these drug-delivery systems cannot accurately deliver the therapeutic cargoes to colon because of early degradation of the polymers at alkaline pH of the small intestine. Here, we describe a precise method of delivering drugs to inflammation sites in colon using an oral drug delivery system. Tacrolimus (FK506)-loaded microspheres were prepared using a thioketal-based polymer that releases drug in response to reactive oxygen species (ROS), which are abundantly produced at the sites of inflammation in acute colitis. Orally-administered FK506-loaded thioketal microspheres (FK506-TKM) led to a substantial accumulation of FK506 in inflamed colon and effectively alleviated dextran-sulfate sodium (DSS)-induced murine colitis. At the molecular level, FK506-TKM significantly inhibited infiltration of CD4+ and CD8+ T lymphocytes in colon and differentiation of CD4+ T cells into Th1 and Th17 cells in colon-draining mesenteric lymph nodes via restricting dendritic cell migration from colon. Our findings indicate orally-administered thioketal-based drug delivery system as a promising means of treating acute inflammatory bowel diseases.

Bispecific nanoparticles (NPs) are conjugated with two antibodies that enhance T cell cytotoxicity by sequentially targeting CD3 and tumor-specific proteins. This interaction redirects T cells to specific tumor antigens and activates them to lyse tumor cells by blocking two different signaling pathways simultaneously. This study developed NP-based bispecific T-cell engagers (nanoBiTEs), which are R848-loaded bispecific poly(lactic-co-glycolic acid) NPs decorated with anti-CD3 antibody targeting T cells and anti-PD-L1 antibody targeting PD-L1 ligands (bis-R848-PLGA-NPs). Bis-R848-PLGA-NPs enhance the immunogenic response in destroying cancer cells by restoring the T cell effector functions. These interactions allow T cells to come in close proximity to the tumor cells. Finally, the release of R848 from PLGA-NPs activates dendritic cells, enhancing T cell activation. In vitro results show maximum internalization of bis-R848-PLGA-NPs in SK-OV3 and B16F10 cell lines, attributed to high PD-L1 expression in both cells. Furthermore, bis-R848-PLGA-NPs-treated CD8

Parkinson's disease (PD) is a debilitating neurodegenerative condition characterized by the loss of dopaminergic neurons within the substantia nigra. The specific molecular mechanisms through which PD-associated neuronal loss occurs remain unclear, and there is no available effective treatment against PD-related neurodegeneration. Resveratrol (RSV) has exhibited promising neuroprotective effects via antioxidant and anti-inflammatory activity. However, its poor bioavailability in the brain represents a challenge for its application in PD treatment. In this study, we synthesized RSV-loaded PLGA nanoparticles (RSV-PLGA-NPs) conjugated with lactoferrin (Lf) to enhance RSV diffusion into the brain and assessed whether this formulation improved the neuroprotective effects of RSV in experimental PD models. The Lf-conjugated RSV-PLGA-NPs (Lf-RSV-PLGA-NPs) exhibited enhanced internalization into SH-SY5Y and human brain microvascular endothelial cells as compared to RSV-PLGA-NPs and free RSV. Further, Lf-RSV-PLGA-NPs were more effective than RSV-PLGA-NPs and free RSV in attenuating the MPP