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The limited infiltration and persistence of chimeric antigen receptor (CAR)-T cells is primarily responsible for their treatment deficits in solid tumors. Here, we present a three-dimensional scaffold, inspired by the physiological process of T-cell proliferation in lymph nodes. This scaffold gathers the function of loading, delivery, activation and expansion for CAR-T cells to enhance their therapeutic effects on solid tumors. This porous device is made from poly(lactic-co-glycolic acid) by a microfluidic technique with the modification of T-cell stimulatory signals, including anti-CD3, anti-CD28 antibodies, as well as cytokines. This scaffold fosters a 50-fold CAR-T cell expansion in vitro and a 15-fold cell expansion in vivo. Particularly, it maintains long-lasting expansion of CAR-T cells for up to 30 days in a cervical tumor model and significantly inhibits the tumor growth. This biomimetic delivery strategy provides a versatile platform of cell delivery and activation for CAR-T cells in treating solid tumors. [ABSTRACT FROM AUTHOR]

Immunogenic cell death (ICD), a dying state of the cells, encompasses the changes in the conformations of cell surface and the release of damage‐associated molecular patterns, which could initiate an adaptive immune response by stimulating the dendritic cells to present antigens to T cells. Advancements in biomaterials, nanomedicine, and micro‐ and nano‐technologies have facilitated the development of effective ICD inducers, but the potential toxicity of these vesicles encountered in drug delivery via intravenous administration hampers their further application. As alternatives, the local drug delivery systems have gained emerging attention due to their ability to prolong the retention of high payloads at the lesions, sequester drugs from harsh environments, overcome biological barriers to exert optimal efficacy, and minimize potential side effects to guarantee bio‐safety. Herein, a brief overview of the local drug delivery techniques used for ICD inducers is provided, explaining how these techniques broaden, alter, and enhance the therapeutic capability while circumventing systemic toxicity at the same time. The historical context and prominent examples of the local administration of ICD inducers are introduced. The complexities, potential pitfalls, and opportunities for local drug delivery techniques in cancer immunotherapy are also discussed. [ABSTRACT FROM AUTHOR]

Lipid nanoparticle‐based drug delivery systems have a profound clinical impact on nucleic acid‐based therapy and vaccination. Recombinant human insulin, a negatively‐charged biomolecule like mRNA, may also be delivered by rationally‐designed positively‐charged lipid nanoparticles with glucose‐sensing elements and be released in a glucose‐responsive manner. Herein, we have designed phenylboronic acid‐based quaternary amine‐type cationic lipids that can self‐assemble into spherical lipid nanoparticles in an aqueous solution. Upon mixing insulin and the lipid nanoparticles, a heterostructured insulin complex is formed immediately arising from the electrostatic attraction. In a hyperglycemia‐relevant glucose solution, lipid nanoparticles become less positively charged over time, leading to reduced attraction and subsequent insulin release. Compared with native insulin, this lipid nanoparticle‐based glucose‐responsive insulin shows prolonged blood glucose regulation ability and blood glucose‐triggered insulin release in a type 1 diabetic mouse model. [ABSTRACT FROM AUTHOR]

Protein and peptide drugs are predominantly administered by injection to achieve high bioavailability, but this greatly compromises patient compliance. Oral and transdermal drug delivery with minimal invasiveness and high adherence represent attractive alternatives to injection administration. However, oral and transdermal administration of bioactive proteins must overcome biological barriers, namely the gastrointestinal and skin barriers, respectively. The rapid development of new materials and technologies promises to address these physiological obstacles. This review provides an overview of the latest advances in oral and transdermal protein delivery, including chemical strategies, synthetic nanoparticles, medical microdevices, and biomimetic systems for oral administration, as well as chemical enhancers, physical approaches, and microneedles in transdermal delivery. We also discuss challenges and future perspectives of the field with a focus on innovation and translation. [ABSTRACT FROM AUTHOR]

Glucose-responsive insulin (GRI) can tremendously facilitate insulin administration via expanding the safe dosage window and reducing injection frequency, as well as enhancing blood glucose control via actively adjusting the insulin release rate. We have previously prepared a robust ion complex-based GRI for type 1 diabetes treatment; however, this complex precipitates easily, which could cause difficulty of injection and inaccuracy of dosage. It remains elusive whether nanoparticulation of this complex could increase suspension stability and retain glucose responsiveness. Herein, we have linked poly (ethylene glycol) (PEG) to 4-carboxy-3-fluorophenylboronic acid (FPBA)-modified poly- ʟ -lysine to obtain PEG-PLL-FPBA. PEG-PLL-FPBA and insulin can form nanosized insulin complex (NIC) with a high insulin loading content and encapsulation efficiency. Of note, the size of the prepared NIC can keep stable for more than 7 days. The NIC showed glucose-stimulated insulin release in vitro with a maximal glucose-responsive index of 400 %. In a streptozotocin (STZ)-induced type 1 diabetic mouse model, the subcutaneously injected NIC could normalize hyperglycemia in 30 min and maintain it normally for 20 h, while minimal toxicity has been identified. [Display omitted] An injectable and stable nanosized formulation has been developed for glucose-responsive insulin delivery. • A stably dispersed and injectable nanosized insulin formulation is prepared. • The nanoparticles can keep size stable at around 100 nm for more than 7 days. • The formulation shows glucose-stimulated insulin release in vitro and in vivo. • The formulation can maintain normoglycemia > 20 h with negligible hypoglycemia. [ABSTRACT FROM AUTHOR]

The dynamic roles of T cells in the immune system to recognize and destroy the infected or mutated cells render T cell therapy a prospective treatment for a variety of diseases including cancer, autoimmune diseases, and allograft rejection. However, the clinical applications of T cell therapy remain unsatisfactory due to the tedious manufacturing process, off-target cytotoxicity, poor cell persistence, and associated adverse effects. To this end, various biomaterials have been introduced to enhance T cell therapy by facilitating proliferation, enhancing local enrichment, prolonging retention, and alleviating side effects. This review highlights the design strategies of biomaterials developed for T cell expansion, enrichment, and delivery as well as their corresponding therapeutic effects. The prospects of biomaterials for enhancing T cell immunotherapy are also discussed in this review. [Display omitted] [ABSTRACT FROM AUTHOR]