Byung-Soo Kim

The development of therapeutic cancer vaccines (TCVs) that provide clinical benefits is challenging mainly due to difficulties in identifying immunogenic tumor antigens and effectively inducing antitumor immunity. Furthermore, there is an urgent need for personalized TCVs because only a limited number of tumor antigens are shared among cancer patients. Several autologous nanovaccines that do not require the identification of immunogenic tumor antigens have been proposed as personalized TCVs. However, these nanovaccines generally require exogenous adjuvants (e.g., Toll-like receptor agonists) to improve vaccine immunogenicity, which raises safety concerns. Here, we present senescent cancer cell-derived nanovesicle (SCCNV) as a personalized TCV that provides patient-specific tumor antigens and improved vaccine immunogenicity without the use of exogenous adjuvants. SCCNVs are prepared by …

Alzheimer’s disease (AD) is a neurodegenerative disease with multifactorial pathogenesis. However, most current therapeutic approaches for AD target a single pathophysiological mechanism, generally resulting in unsatisfactory therapeutic outcomes. Recently, mesenchymal stem cell (MSC) therapy, which targets multiple pathological mechanisms of AD, has been explored as a novel treatment. However, the low brain retention efficiency of administered MSCs limits their therapeutic efficacy. In addition, autologous MSCs from AD patients may have poor therapeutic abilities. Here, we overcome these limitations by developing iron oxide nanoparticle (IONP)-incorporated human Wharton’s jelly-derived MSCs (MSC-IONPs). IONPs promote therapeutic molecule expression in MSCs. Following intracerebroventricular injection, MSC-IONPs showed a higher brain retention efficiency under magnetic guidance. This …

Commencing with the breakdown of immune tolerance, multiple pathogenic factors, including synovial inflammation and harmful cytokines, are conjointly involved in the progression of rheumatoid arthritis. Intervening to mitigate some of these factors can bring a short-term therapeutic effect, but other unresolved factors will continue to aggravate the disease. Here we developed a ceria nanoparticle-immobilized mesenchymal stem cell nanovesicle hybrid system to address multiple factors in rheumatoid arthritis. Each component of this nanohybrid works individually and also synergistically, resulting in comprehensive treatment. Alleviation of inflammation and modulation of the tissue environment into an immunotolerant-favourable state are combined to recover the immune system by bridging innate and adaptive immunity. The therapy is shown to successfully treat and prevent rheumatoid arthritis by relieving the main …

Alzheimer's disease (AD), the most common cause of dementia, is a complex condition characterized by multiple pathophysiological mechanisms including amyloid‐β (Aβ) plaque accumulation and neuroinflammation in the brain. The current immunotherapy approaches, such as anti‐Aβ monoclonal antibody (mAb) therapy, Aβ vaccines, and adoptive regulatory T (Treg) cell transfer, target a single pathophysiological mechanism, which may lead to unsatisfactory therapeutic efficacy. Furthermore, Aβ vaccines often induce T helper 1 (Th1) cell‐mediated inflammatory responses. Here, a nanovaccine composed of lipid nanoparticles loaded with Aβ peptides and rapamycin is developed, which targets multiple pathophysiological mechanisms, exhibits the combined effects of anti‐Aβ antibody therapy and adoptive Aβ‐specific Treg cell transfer, and can overcome the limitations of current immunotherapy approaches for …

Conventional approaches to developing therapeutic cancer vaccines that primarily activate tumor‐specific T cells via dendritic cells (DCs) often demonstrate limited efficacy due to the suboptimal activation of these T cells. To address this limitation, here a therapeutic cancer nanovaccine is developed that enhances T cell responses by interacting with both DCs and T cells. The nanovaccine is based on a cancer cell membrane nanoparticle (CCM‐MPLA) that utilizes monophosphoryl lipid A (MPLA) as an adjuvant. To allow direct interaction between the nanovaccine and tumor‐specific T cells, anti‐CD28 antibodies (aCD28) are conjugated onto CCM‐MPLA, resulting in CCM–MPLA–aCD28. This nanovaccine activates tumor‐specific CD8+ T cells in both the presence and absence of DCs. Compared with nanovaccines that interact with either DCs (CCM–MPLA) or T cells (CCM–aCD28), CCM–MPLA–aCD28 …

To demonstrate potent efficacy, a cancer vaccine needs to activate both innate and adaptive immune cells. Personalized cancer vaccine strategies often require the identification of patient‐specific neoantigens; however, the clonal and mutational heterogeneity of cancer cells presents inherent challenges. Here, extracellular nanovesicles derived from alpha‐galactosylceramide‐conjugated autologous acute myeloid leukemia (AML) cells (ECNV‐αGC) are presented as a personalized therapeutic vaccine that activates both innate and adaptive immune responses, bypassing the need to identify patient‐specific neoantigens. ECNV‐αGC vaccination directly engages with and activates both invariant natural killer T (iNKT) cells and leukemia‐specific CD8+ T cells in mice with AML, thereby promoting long‐term anti‐leukemic immune memory. ECNV‐αGC sufficiently serves as an antigen‐presenting platform that can …

Various immune cells participate in repair and regeneration following tissue injury or damage, orchestrating tissue inflammation and regeneration processes. A deeper understanding of the immune system’s involvement in tissue repair and regeneration is critical for the development of successful reparatory and regenerative strategies. Here we review recent technologies that facilitate cell-based and biomaterial-based modulation of the immune systems for tissue repair and regeneration. First, we summarize the roles of various types of immune cells in tissue repair. Second, we review the principle, examples, and limitations of regulatory T (Treg) cell-based therapy, a representative cell-based immunotherapy. Finally, we discuss biomaterial-based immunotherapy strategies that aim to modulate immune cells using various biomaterials for tissue repair and regeneration.

The vast majority of drug-eluting stents (DES) elute either sirolimus or one of its analogues. While limus drugs stymie vascular smooth muscle cell (VSMC) proliferation to prevent in-stent restenosis, their antiproliferative nature is indiscriminate and limits healing of the endothelium in stented vessels, increasing the risk of late-stent thrombosis. Oxidative stress, which is associated with vascular injury from stent implantation, can induce VSMCs to undergo senescence, and senescent VSMCs can produce pro-inflammatory cytokines capable of inducing proliferation of neighboring nonsenescent VSMCs. We explored the potential of senolytic therapy, which involves the selective elimination of senescent cells, in the form of a senolytic-eluting stent (SES) for interventional cardiology. Oxidative stress was modeled in vitro by exposing VSMCs to H2O2, and H2O2-mediated senescence was evaluated by cytochemical …

Despite the clinically proven efficacies of immune checkpoint blockades, including anti‐cytotoxic T lymphocyte‐associated protein 4 antibody (αCTLA‐4), the low response rate and immune‐related adverse events (irAEs) in cancer patients represent major drawbacks of the therapy. These drawbacks of αCTLA‐4 therapy are mainly due to the suboptimal activation of tumor‐specific cytotoxic T lymphocytes (CTLs) and the systemic nonspecific activation of T cells. To overcome such drawbacks, αCTLA‐4 is delivered by dendritic cell‐derived nanovesicles presenting tumor antigens (DCNV‐TAs) that exclusively interact with tumor‐specific T cells, leading to selective activation of tumor‐specific CTLs. Compared to conventional αCTLA‐4 therapy, treatment with αCTLA‐4‐conjugated DCNV‐TAs significantly inhibits tumor growth and reduces irAEs in syngeneic tumor‐bearing mice. This study demonstrates that the …

Intervertebral disc (IVD) degeneration (IVDD) is a leading cause of chronic low back pain. There is a strong clinical demand for more effective treatments for IVDD as conventional treatments provide only symptomatic relief rather than arresting IVDD progression. This study shows that senolytic therapy with local drug delivery can inhibit IVDD and restore IVD integrity. ABT263, a senolytic drug, is loaded in poly(lactic‐co‐glycolic acid) nanoparticles (PLGA‐ABT) and intradiscally administered into injury‐induced IVDD rat models. The single intradiscal injection of PLGA‐ABT may enable local delivery of the drug to avascular IVD, prevention of potential systemic toxicity caused by systemic administration of senolytic drug, and morbidity caused by repetitive injections of free drug into the IVD. The strategy results in the selective elimination of senescent cells from the degenerative IVD, reduces expressions of pro …

Microphysiological systems (MPSs), based on microfabrication technologies and cell culture, can faithfully recapitulate the complex physiology of various tissues. However, 3D tissues formed using MPS have limitations in size and accessibility; their use in regenerative medicine is, therefore, still challenging. Here, an MPS‐inspired scale‐up vascularized engineered tissue construct that can be used in regenerative medicine is designed. Endothelial cell‐laden hydrogels are sandwiched between two through‐hole membranes. The microhole array in the through‐hole membranes enables the molecular transport across the hydrogel layer, allowing long‐term cell culture. Furthermore, the time‐controlled delamination of through‐hole membranes enables the harvesting of cell‐cultured hydrogel constructs without damaging the capillary network. Importantly, when the tissue constructs are implanted in a mouse …

Local inflammation in the joint is considered to contribute to osteoarthritis (OA) progression. Here, we describe an immunomodulating nanoparticle for OA treatment. Intradermal injection of lipid nanoparticles (LNPs) loaded with type II collagen (Col II) and rapamycin (LNP-Col II-R) into OA mice effectively induced Col II–specific anti-inflammatory regulatory T cells, substantially increased anti-inflammatory cytokine expression, and reduced inflammatory immune cells and proinflammatory cytokine expression in the joints. Consequently, LNP-Col II-R injection inhibited chondrocyte apoptosis and cartilage matrix degradation and relieved pain, while injection of LNPs loaded with a control peptide and rapamycin did not induce these events. Adoptive transfer of CD4+CD25+ T cells isolated from LNP-Col II-R–injected mice suggested that Tregs induced by LNP-Col II-R injection were likely responsible for the therapeutic …

The unique biological characteristics and promising clinical potential of extracellular vesicles (EVs) have galvanized EV applications for regenerative medicine. Recognized as important mediators of intercellular communication, naturally secreted EVs have the potential, as innate biotherapeutics, to promote tissue regeneration. Although EVs have emerged as novel therapeutic agents, challenges related to the clinical transition have led to further functionalization. In recent years, various engineering approaches such as preconditioning, drug loading, and surface modification have been developed to potentiate the therapeutic outcomes of EVs. Also, limitations of natural EVs have been addressed by the development of artificial EVs that offer advantages in terms of production yield and isolation methodologies. In this review, an updated overview of current techniques is provided for the functionalization of natural …

Myocardial ischemia-reperfusion (IR) generates stress-induced senescent cells (SISCs) that play an important role in the pathophysiology of adverse cardiac remodeling and heart failure via secretion of pro-inflammatory molecules and matrix-degrading proteases. Thus, removal of senescent cells using a senolytic drug could be a potentially effective treatment. However, clinical studies on cancer treatment with a senolytic drug have revealed that systemic administration of a senolytic drug often causes systemic toxicity. Herein we show for the first time that local delivery of a senolytic drug can effectively treat myocardial IR injury. We found that biodegradable poly(lactic-co-glycolic acid) nanoparticle-based local delivery of a senolytic drug (ABT263-PLGA) successfully eliminated SISCs in the IR-injured rat hearts without systemic toxicity. Consequently, the treatment ameliorated inflammatory responses and attenuated …

Severe cardiac damage following myocardial infarction (MI) causes excessive inflammation, which sustains tissue damage and often induces adverse cardiac remodeling toward cardiac function impairment and heart failure. Timely resolution of post‐MI inflammation may prevent cardiac remodeling and development of heart failure. Cell therapy approaches for MI are time‐consuming and costly, and have shown marginal efficacy in clinical trials. Here, nanoparticles targeting the immune system to attenuate excessive inflammation in infarcted myocardium are presented. Liposomal nanoparticles loaded with MI antigens and rapamycin (L‐Ag/R) enable effective induction of tolerogenic dendritic cells presenting the antigens and subsequent induction of antigen‐specific regulatory T cells (Tregs). Impressively, intradermal injection of L‐Ag/R into acute MI mice attenuates inflammation in the myocardium by inducing …

Chimeric antigen receptor‐T (CAR‐T) cell immunotherapy has shown impressive clinical outcomes for hematologic malignancies. However, its broader applications are challenged due to its complex ex vivo cell‐manufacturing procedures and low therapeutic efficacy against solid tumors. The limited therapeutic effects are partially due to limited CAR‐T cell infiltration to solid tumors and inactivation of CAR‐T cells by the immunosuppressive tumor microenvironment. Here, a facile approach is presented to in vivo program macrophages, which can intrinsically penetrate solid tumors, into CAR‐M1 macrophages displaying enhanced cancer‐directed phagocytosis and anti‐tumor activity. In vivo injected nanocomplexes of macrophage‐targeting nanocarriers and CAR‐interferon‐γ‐encoding plasmid DNA induce CAR‐M1 macrophages that are capable of CAR‐mediated cancer phagocytosis, anti‐tumor …

Defatted sesame meal (DSM) is a source rich in glycosylated lignans and bioactive compounds. Hydrothermal (HT) processes with and without added CO2 were applied to recover these bioactive compounds. The extractions were performed from 120 to 180 °C with a solid-to-solvent ratio of 1:20 (w/w). The bioactivities, expressed in terms of the total phenol (TP) and total flavonoid (TF) contents in the HT extracts were enhanced 5- and 2.5-fold, respectively. The addition of CO2 enabled the recovery of more bioactive compounds with better antioxidant activities than those obtained using conventional extraction methods. In-vitro antioxidant and anticancer effects were evaluated for both the HT extracts and conventional extracts, where promising anticancer activity was observed with little effect on normal cells.

Background Various cell-culture systems have been used to evaluate drug toxicity in vitro. However, factors that affect cytotoxicity outcomes in drug toxicity evaluation systems remain elusive. In this study, we used multilayered sheets of cardiac-mimetic cells, which were reprogrammed from human fibroblasts, to investigate the effects of the layer number on drug cytotoxicity outcomes. Methods Cell sheets of cardiac-mimetic cells were fabricated by reprogramming of human fibroblasts into cardiac-mimetic cells via coculture with cardiac cells and electric stimulation, as previously described. Double-layered cell sheets were prepared by stacking the cell sheets. The mono- and double-layered cell sheets were treated with 5-fluorouracil (5-FU), an anticancer drug, in vitro. Subsequently, apoptosis and lipid peroxidation were analyzed. Furthermore, effects of …

Nanoparticles have been used for effectively delivering imaging agents and therapeutic drugs into stem cells. However, nanoparticles are not sufficiently internalized into stem cells; thus, new delivery method of nanoparticles into stem cells is urgently needed. Herein, we develop bicyclo[6.1.0]nonyne (BCN)-conjugated gold nanoparticles (BCN-AuNPs), which can be bioorthogonally conjugated to azide (−N3) groups on the surface of metabolically engineered stem cells via bioorthogonal click chemistry. For incorporating azide groups on the cell surface, first, human adipose-derived mesenchymal stem cells (hMSCs) were metabolically engineered with N-azidoacetylmannosamine-tetraacylated (Ac4ManNAz). Second, clickable BCN-AuNPs were bioorthogonally conjugated to azide groups on Ac4ManNAz-treated hMSCs. Importantly, a large amount of BCN-AuNPs was specifically conjugated to metabolically …

BACKGROUNDFerroptosis is an iron-dependent, non-apoptotic programmed cell death. Cellular senescence contributes to aging and various age-related diseases through the expression of a senescence-associated secretory phenotype (SASP). Senescent cells are often resistant to ferroptosis via increased ferritin and impaired ferritinophagy. In this study, we investigated whether treatment with JQ1 could remove senescent cells by inducing ferroptosis.METHODSSenescence of human dermal fibroblasts was induced in vitro by treating the cells with bleomycin. The senolytic effects of JQ1 were evaluated using a SA-β gal assay, annexin V analysis, cell counting kit-8 assay, and qRT-PCR. Ferroptosis following JQ1 treatment was evaluated with qRT-PCR and BODIPY staining. RESULTSAt a certain range of JQ1 concentrations, JQ1 treatment reduced the viability of bleomycin-treated cells (senescent cells) but did …