Yu Seok Youn

Cluster of differentiation 44 (CD44) is highly expressed in ovarian cancer (OC) and plays a critical role in cancer stem cell (CSC) maintenance, tumor initiation, and chemoresistance, making it an attractive therapeutic target. Herein, a CD44‐targeted antibody‐drug conjugate (ADC), CD44‐VC‐DOX, is developed by conjugating doxorubicin (DOX) to an anti‐CD44 monoclonal antibody using a cathepsin‐cleavable MC‐VC‐PAB linker for selective intracellular drug release in CD44‐positive tumor cells. Physicochemical characterization confirms successful conjugation, high stability, and an optimal drug‐to‐antibody ratio. CD44‐VC‐DOX exhibit selective binding and rapid internalization in CD44‐overexpressing OC cells resulting in potent cytotoxicity, apoptosis induction, and G2/M cell‐cycle arrest. Importantly, CD44‐VC‐DOX effectively suppresses CSC‐associated phenotypes, including tumorsphere formation, tumor‐initiating frequency, CD44 ⁺ CD133 ⁺ CSC populations, ALDH‐positive cells, and stemness‐related gene expression. In addition, CD44‐VC‐DOX reduces hypoxia‐associated HIF‐1α expression, indicating disruption of the CSC‐supportive tumor microenvironment. In vivo, CD44‐VC‐DOX demonstrates efficient tumor targeting, significant tumor growth inhibition, and minimal systemic toxicity. Transcriptomic profiling further reveals coordinated suppression of CSC‐associated and oncogenic pathways, including PI3K/AKT, MYC signaling, E2F targets, DNA repair, and stemness‐related transcriptional programs, supporting effective depletion of tumor‐initiating CSC populations and reduced tumor adaptability. Collectively, these findings highlight CD44‐VC‐DOX as a promising precision therapeutic strategy for targeting CSC‐driven OC.

Antigen‐presenting cells (APCs), particularly dendritic cells (DCs), play key roles in activating T cells for enhanced immune response in cancer immunotherapy. In cancer progression, an immunosuppressive tumor microenvironment (TME) is gradually developed, shielding tumor cells from immune surveillance. One of the defects created by the TME is the presence of dysfunctional DCs, which triggers failures in antigen recognition, processing, and presentation to T cells, inducing the impairment of anti‐tumor immune responses. The demand for ex vivo T cell activation and expansion by the replacement of autologous DCs is imperative in adoptive cell therapy (ACT) due to the limited availability and the laborious isolation of natural DCs. Therefore, the fabrication of artificial APCs (aAPCs) mimicking the function of natural DCs holds promise for cancer immunotherapy, especially in ACT. This review concentrates on the design of aAPCs using the principles of cell signaling for the immunological synapse: T cell receptor (TCR)‐specific activation (signal 1), co‐stimulatory signal (signal 2), and cytokine‐mediated signal (signal 3). Particularly, the customization of size, shape, stiffness, density, and mobility of ligands, as well as the dimension of activating engagers for the optimization of aAPCs, is also discussed.

Recently, nanovaccine-based immunotherapy has been robustly investigated due to its potential in governing the immune response and generating long-term protective immunity. However, the presentation of a tumor peptide-major histocompatibility complex to T lymphocytes is still a challenge that needs to be addressed for eliciting potent antitumor immunity. Type 1 conventional dendritic cell (cDC1) subset is of particular interest due to its pivotal contribution in the cross-presentation of exogenous antigens to CD8⁺ T cells. Here, the DC-derived nanovaccine (denoted as Si9GM) selectively targets cDC1s with marginal loss of premature antigen release for effective stimulator of interferon genes (STING)-mediated antigen cross-presentation. Bone marrow dendritic cell (BMDC)-derived membranes, conjugated to cDC1-specific antibody (αCLEC9A) and binding to tumor peptide (OVA_257-264), are coated onto dendrimer-like polyethylenimine (PEI)-grafted silica nanoparticles. Distinct molecular weight-cargos (αCLEC9A-OVA_257-264 conjugates and 2'3'-cGAMP STING agonists) are loaded in hierarchical center-radial pores that enables lysosome escape for potent antigen-cross presentation and activates interferon type I, respectively. Impressively, Si9GM vaccination leads to the upregulation of cytotoxic T cells, a reduction in tumor regulatory T cells (Tregs), M1/M2 macrophage polarization, and immune response that synergizes with αPD-1 immune checkpoint blockade. This nanovaccine fulfills a dual role for both direct T cell activation as an artificial antigen-presenting cell and DC subset maturation, indicating its utility in clinical therapy and precision medicine.

Chemodynamic therapy (CDT) has emerged as a novel approach to overcome cancer resistance and enhance anticancer efficacy. Despite the considerable effort devoted to current chemodynamic therapeutic agents, developing efficient delivery systems to induce ferroptosis remains demanding due to their limited efficacy and lack of selectivity. Herein, an iron‐based single‐atom upconversion photocatalyst (UmFe‐OA@hPM) mimicking natural horseradish peroxidases has been developed. This nanoformulation not only targets tumors via the existence of a hybrid platelet membrane (hPM) coating but also generates excessive hydroxyl radicals in response to both tumor microenvironment and external laser irradiation. This nanoenzyme overcomes the low tissue penetration of UV light, which sensitizes the iron‐doped graphitic carbon nitride network, attributed to the unique anti‐Stokes shift from infrared to UV displayed by upconversion nanoparticles. Together with an increase in intracellular polyunsaturated fatty acid accumulation induced by oleanolic acid (OA), lipid peroxidation is significantly elevated, leading to the enhancement of CDT. UmFe‐OA@hPM is demonstrated to induce significant ferroptosis in vitro, superior antitumor efficacy in breast cancer mouse models, and suppression of metastasis status when incorporated with an immune checkpoint blockade. These findings provide a potential strategy for developing a precisely controlled CDT to deal with aggressive cancers, especially in combination with immunotherapy.

Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory and fibrotic response-driven lung disease that is difficult to cure because it manifests excessive profibrotic cytokines (e.g., TGF-β), activated myofibroblasts, and accumulated extracellular matrix (ECM). In an attempt to develop an inhalation formulation with enhanced antifibrotic efficacy, we sought to fabricate unique aerosolizable inhaled microgels (μGel) that contain nintedanib-poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs; n-PN) and pirfenidone-liposomes (p-LP). The aero-μGel was ∼12 μm, resisted phagocytosis by alveolar macrophages in vitro and in vivo, and protected inner-entrapped n-PN and p-LP. The n-PN/p-LP@aero-μGel caused enhanced/extended antifibrotic efficacy in a bleomycin-induced pulmonary fibrosis mouse presumably due to prolonged lung residence. Consequently, the results obtained by intratracheal aerosol insufflation of our n-PN/p-LP@aero-μGel twice a week were much better than those by as many as seven doses of single or mixed applications of n-PN or p-LP. The antifibrotic/pharmacokinetic results for the n-PN/p-LP@aero-μGel included reduced fibrosis progression, restored lung physiological functions, deactivated myofibroblasts, inhibited TGF-β progression, and suppressed ECM component production (collagen I and α-SMA) along with prolonged lung retention time. We believe that our n-PN/p-LP@aero-μGel increased the local availability of both nintedanib and pirfenidone due to evasion of alveolar macrophage phagocytosis and prolonged lung retention with reduced systemic distribution. Through this approach, our inhalation formulation subsequently attenuated fibrosis progression and improved lung function. Importantly, these results hold profound implications in the therapeutic potential of our n-PN/p-LP@aero-μGel to serve as a clinically promising platform, providing significant advancements for improved treatment of many respiratory diseases including IFP.