Tumor-Infiltrating Lymphocyte Therapy by Local Delivery of an mRNA Encoding Membrane-Anchored Anti-CD3 Single-Chain Variable Fragment.

Tumor-infiltrating lymphocyte (TIL) therapy has shown promising responses in clinical trials for highly aggressive cancers such as advanced melanoma and metastatic colorectal cancer. However, TIL therapy is still limited in clinical practice due to the complex cell preparation process. Here, we report an " TIL therapy" for the treatment of solid tumors.

Intratumoral adoptive transfer of inflammatory macrophages engineered by co-activating TLR and STING signaling pathways exhibits robust antitumor activity.

Despite the success of chimeric antigen receptor (CAR) T cells in hematologic malignancies, adoptive cell therapy (ACT) has not been effective in treating solid tumors. Here, we developed an inflammatory macrophage-based ACT to effectively treat solid tumors. We engineered inflammatory macrophages to enhance their antitumor activities, including proinflammatory cytokine secretion and co-stimulatory molecule expression by co-activating toll-like receptor and stimulator of interferon genes signaling pathways.

Porous Silicon-Based Nanomedicine for Simultaneous Management of Joint Inflammation and Bone Erosion in Rheumatoid Arthritis.

The lack of drugs that target both disease progression and tissue preservation makes it difficult to effectively manage rheumatoid arthritis (RA). Here, we report a porous silicon-based nanomedicine that efficiently delivers an antirheumatic drug to inflamed synovium while degrading into bone-remodeling products. Methotrexate (MTX) is loaded into the porous silicon nanoparticles using a calcium silicate based condenser chemistry.

Coimmunomodulation of tumor and tumor-draining lymph nodes during in situ vaccination promotes antitumor immunity.

In situ vaccination has demonstrated the feasibility of priming local immunity for systemic antitumor responses. Although direct intratumoral (IT) delivery of adjuvant is the mainstay, tumor-draining lymph nodes (TDLNs) also play essential roles in antitumor immunity. We report that directing an adjuvant to both tumors and TDLNs during in situ vaccination can induce robust antitumor responses.

Polypeptide-Based K Ionophore as a Strong Immunogenic Cell Death Inducer for Cancer Immunotherapy.

Immunogenic cell death (ICD) is a key factor for generating antitumor immunity. Endoplasmic reticulum (ER) stress triggers the release of damage-associated molecular patterns (DAMPs), thus inducing immunogenicity. We developed a polypeptide-based K ionophore that perturbed ion homeostasis and elicited a prolonged ER stress.

Management of lymph node metastasis via local chemotherapy can prevent distant metastasis and improve survival in mice.

Management of lymph node metastasis (LNM) by conventional modalities such as radiotherapy and systemic chemotherapy exhibit limited LNM selectivity and therefore can cause off-target adverse events. While development of LNM-specific drug delivery systems has tremendous potential to provide a safer treatment modality and improve cancer treatment, precise assessment of therapeutic efficacy and implications has been challenging due to lack of a suitable preclinical model. Here, we established an experimental LNM model in mice by directly seeding cancer cells into a lymph node (LN), which developed spontaneous LNM-borne distant metastasis (DM) in the absence of a primary tumor.

Nanomedicine for the Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that results in severe inflammatory microenvironments in the joint tissues. In clinics, disease-modifying antirheumatic drugs (DMARDs) are generally prescribed to patients with RA, but their long-term use often shows toxicity in some organs such as the gastrointestinal system, skin, and kidneys and immunosuppression-mediated infection. Nanomedicine has emerged as a new therapeutic strategy to efficiently localize the drugs in inflamed joints for the treatment of RA.

Liposomal borrelidin for treatment of metastatic breast cancer.

Borrelidin is an inhibitor of threonyl-tRNA synthetase with both anticancer and antiangiogenic activities. Although borrelidin could be a potent drug that can treat metastatic cancer through synergistic therapeutic effects, its severe liver toxicity has limited the use for cancer therapeutics. In this study, we developed a liposomal formulation of borrelidin to treat metastatic breast cancer effectively through its combined anticancer and antiangiogenic effects while reducing the potential liver toxicity.

Effective Retinal Penetration of Lipophilic and Lipid-Conjugated Hydrophilic Agents Delivered by Engineered Liposomes.

Efficient delivery of drugs to the retina is critical but difficult to achieve with current methods. There have been a number of attempts to use intravitreal injection of liposomes, artificial vesicles composed of a phospholipid bilayer, to overcome the limitations of conventional intravitreal injection (short retention time, toxicity, poor penetration, etc.).

Cellular Engineering with Membrane Fusogenic Liposomes to Produce Functionalized Extracellular Vesicles.

Engineering of extracellular vesicles (EVs) without affecting biological functions remains a challenge, limiting the broad applications of EVs in biomedicine. Here, we report a method to equip EVs with various functional agents, including fluorophores, drugs, lipids, and bio-orthogonal chemicals, in an efficient and controlled manner by engineering parental cells with membrane fusogenic liposomes, while keeping the EVs intact. As a demonstration of how this method can be applied, we prepared EVs containing azide-lipids, and conjugated them with targeting peptides using copper-free click chemistry to enhance targeting efficacy to cancer cells.

Immunoglobulin Fc-fused, neuropilin-1-specific peptide shows efficient tumor tissue penetration and inhibits tumor growth via anti-angiogenesis.

Neuropilin-1 (NRP1) receptor, involved in vascular endothelial growth factor (VEGF)-mediated vascular permeability and tumor angiogenesis, is targeted by peptides that bind to its VEGF-binding site. However, these peptides also cross-react with the structurally related receptor, NRP2. Here, we describe an immunoglobulin Fc-fused peptide, Fc-TPP11, which specifically binds to the VEGF-binding site of NRP1 with approximately 2nM affinity, but negligibly to that of NRP2.