To achieve deep tumor penetration of large-sized nanoparticles (NPs), we have developed a reversible swelling-shrinking nanogel in response to pH variation for a sequential intra-intercellular NP delivery. The nanogel had a crosslinked polyelectrolyte core, consisting of N-lysinal-N'-succinyl chitosan and poly(N-isopropylacrylamide), and a crosslinked bovine serum albumin shell, which was able to swell in an acidic environment and shrink back under neutral conditions. The swelling resulted in a rapid release of the encapsulated chemotherapeutics in the cancer cells for efficient cytotoxicity. After being liberated from the dead cells, the contractive nanogel could infect neighboring cancer cells closer to the center of the tumor tissue.

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Abstract— The combination of steady‐state and time‐resolved quenching experiments was employed to study the aggregation behavior of sodium cholate at concentrations below 50 mAf. Naphthalene, anthracene and pyrene were used as fluorescent probe molecules, and protection by the aggregates from aqueous quenchers, as well as the onset of aggregation at low sodium cholate concentrations, was dependent on the shape of the probes. Protection from aqueous quenchers was inferred by comparing the efficiency for dynamic quenching in the absence and presence of sodium cholate and was best for naphthalene followed by pyrene and anthracene. Static quenching was observed, suggesting that probe molecules are located in an aggregate environment that also contains iodide. The incorporation of pyrene at low sodium cholate concentrations, as well as the small degree of static quenching observed, suggest that the shape complementarity, i.e. hydrophobic surface and packing, between pyrene and sodium cholate is optimum for aggregate formation.

Neutrophils are implicated in numerous inflammatory diseases, and especially in acute ischemic stroke (AIS). The unchecked migration of neutrophils into cerebral ischemic regions, and their subsequent release of reactive oxygen species, are considered the primary causes of reperfusion injury following AIS. Reducing the infiltration of inflammatory neutrophils may therefore be a useful therapy for AIS. Here, inspired by the specific cell–cell recognition that occurs between platelets and inflammatory neutrophils, we describe platelet-mimetic nanoparticles (PTNPs) that can be used to directly recognize, intervene, and monitor inflammatory neutrophils in the AIS treatment and therapeutic evaluation. We demonstrate that PTNPs, coloaded with piceatannol, a selective spleen tyrosine kinase inhibitor, and superparamagnetic iron oxide (SPIO), a T2 contrast agent, can successfully recognize adherent neutrophils via platelet membrane coating. The loaded piceatannol could then be delivered to adherent neutrophils and detach them into circulation, thus decreasing neutrophil infiltration and reducing infarct size. Moreover, when coupled with magnetic resonance imaging, internalized SPIO could be used to monitor the inflammatory neutrophils, associated with therapeutic effects, in real time. This approach is an innovative method for both the treatment and therapeutic evaluation of AIS, and provides new insights into how to treat and monitor neutrophil-associated diseases.

Treatment of solid tumors with T cell therapy has yielded limited therapeutic benefits to date. Although T cell therapy in combination with proinflammatory cytokines or immune checkpoints inhibitors has demonstrated preclinical and clinical successes in a subset of solid tumors, unsatisfactory results and severe toxicities necessitate the development of effective and safe combinatorial strategies. Here, the liposomal avasimibe (a metabolism-modulating drug) was clicked onto the T cell surface by lipid insertion without disturbing the physiological functions of the T cell. Avasimibe could be restrained on the T cell surface during circulation and extravasation and locally released to increase the concentration of cholesterol in the T cell membrane, which induced rapid T cell receptor clustering and sustained T cell activation. Treatment with surface anchor-engineered T cells, including mouse T cell receptor transgenic CD8+ T cells or human chimeric antigen receptor T cells, resulted in superior antitumor efficacy in mouse models of melanoma and glioblastoma. Glioblastoma was completely eradicated in three of the five mice receiving surface anchor-engineered chimeric antigen receptor T cells, whereas mice in other treatment groups survived no more than 64 days. Moreover, the administration of engineered T cells showed no obvious systemic side effects. These cell-surface anchor-engineered T cells hold translational potential because of their simple generation and their safety profile.