This study introduces a novel cross-linking strategy capable of successfully stabilizing CaP nanoparticles and stimuli-responsive small interfering RNA (siRNA) release. We synthesized a polysaccharide derivative thiolated hyaluronic acid (HA-SH), which was slightly modified but multifunctional and developed a smart redox-responsive delivery system. siRNA was efficaciously condensed by calcium phosphate (CaP) via electrostatic interaction to form a positively charged inner "core". Disulfide cross-linked HA (HA-ss-HA) was formed and played a role as an anionic outer "shell" to stabilize the CaP core. We demonstrated that the nanoparticles were stable both in the storage milieu and systemic circulation, thus overcoming the most serious disadvantage of CaP nanoparticles for gene delivery. Meanwhile, this smart system could selectively release siRNA into the cytosol by both a GSH-triggered disassembly and successful endosomal escape. Therefore, the hybrid delivery system achieved an 80% gene-silencing efficiency in vitro for both luciferase and Bcl2. Silencing of Bcl2 resulted in dramatic apoptosis of B16F10 cells. Besides, equipped with the tumor-targeting component HA, the nanoparticles significantly suppressed the growth of B16F10 xenograft tumor in mice. The anionic HA-ss-HA-equipped nanoparticles showed no apparent toxicity in vitro or in vivo, as well as showed a high transfection efficiency. Taken together, this redox-responsive, tumor-targeting smart anionic nanoparticle holds great promise for exploitation in functionalized siRNA delivery and tumor therapy.
Protein-based theranostic agents (PBTAs) exhibit superior performance in the diagnosis and therapy of cancers. However, the in vivo applications of PBTA are largely limited by undesired accumulation, penetration, or selectivity. Here, an ATP-supersensitive protein cluster is fabricated for promoting PBTA delivery and enhancing magnetic resonance imaging (MRI)-guided tumor photothermal therapy. Gd 3+ -and CuS-coloaded small bovine serum albumin nanoparticles (GdCuB) are synthesized as the model protein with a size of 9 nm and are encapsulated into charge switchable polycations (DEP) to form DEP/ GdCuB nanoclusters of 120 nm. In blood circulation, DEP/GdCuB significantly extends the half-lifetime and thereby enhances the tumor accumulation of GdCuB. When the clusters reach the tumor site, the extracellular adenosine triphosphate (ATP) can effectively trigger the release of GdCuB, resulting in tumoral deep penetration as well as the activation of T 1 -weighted MRI (r 1 value switched from 2.8 × 10 −3 to 11.8 × 10 −3 m −1 s −1 ). Furthermore, this delivery strategy also improves the tumoral photothermal therapy efficacy with the MRI-guided therapy. The study of ATP-activated nanoclusters develops a novel strategy for tumor deep penetration and on/off imaging of PBTA by size switchable technology, and reveals the potential for MRI-guided therapy of cancers.
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