Overactivated T cells and overproduced pro‐inflammatory cytokines form a self‐amplified signaling loop to continuously exacerbate the dysregulated inflammatory response and propel the progression of autoimmune diseases (AIDs). Herein, immuno‐engineered nanodecoys (NDs) based on poly(lactic‐co‐glycolic acid) nanoparticles coated with programmed death‐ligand 1 (PD‐L1)‐expressing macrophage membrane (PRM) are developed to mediate multi‐target interruption of the self‐promoted inflammatory cascade in AIDs. The PRM collected from IFN‐γ‐treated RAW 264.7 cells possesses elevated surface levels of adhesion molecule receptors and pro‐inflammatory cytokine receptors, and, thus, systemically administered PRM NDs afford higher accumulation level in inflamed tissues and stronger scavenging efficiency toward multiple pro‐inflammatory cytokines. More importantly, IFN‐γ treatment induces remarkable PD‐L1 expression on PRM, thereby allowing PRM NDs to bind membrane‐bound programmed death‐1 (PD‐1) on CD4+ T cell surfaces or neutralize free soluble PD‐1, which reconstructs the PD‐1/PD‐L1 inhibitory axis to suppress CD4+ T cell activation and restore immune tolerance. As such, PRM NDs provoke potent and cooperative anti‐inflammatory and immune‐suppressive efficacies to alleviate autoimmune damages in Zymosan A‐induced arthritis mice and dextran sulfate sodium‐induced ulcerative colitis mice. This study provides an enlightened example for the immuno‐engineering of cell‐membrane‐based NDs, rendering promising implications into the treatment of AIDs via multi‐target immune‐modulation.
The success of intracellular protein therapy demands efficient delivery and selective protein activity in diseased cells. Therefore, a cascaded nanozymogen consisting of a hypoxia‐activatable pro‐protein, a hypoxia‐inducing protein, and a hypoxia‐strengthened intracellular protein delivery nanovehicle was developed. RPAB, an enzymatically inactive pro‐protein of RNase, reversibly caged with hypoxia‐cleavable azobenzene, was delivered with glucose oxidase (GOx) using hypoxia‐responsive nanocomplexes (NCs) consisting of azobenzene‐cross‐linked oligoethylenimine (AOEI) and hyaluronic acid (HA). Upon NC‐mediated delivery into cancer cells, GOx catalyzed glucose decomposition and aggravated tumoral hypoxia, which drove the recovery of RPAB back to the hydrolytically active RNase and expedited the degradation of AOEI to release more protein cargoes. Thus, the catalytic reaction of the nanozymogen was self‐accelerated and self‐cycled, ultimately leading to a cooperative anti‐cancer effect between GOx‐mediated starvation therapy and RNase‐mediated pro‐apoptotic therapy.
Systemic immunosuppression mediated by tumor‐derived exosomes is an important cause for the resistance of immune checkpoint blockade (ICB) therapy. Herein, self‐adaptive platelet (PLT) pharmacytes are engineered to mediate cascaded delivery of exosome‐inhibiting siRNA and anti‐PD‐L1 (aPDL1) toward synergized antitumor immunity. In the pharmacytes, polycationic nanocomplexes (NCs) assembled from Rab27 siRNA (siRab) and a membrane‐penetrating polypeptide are encapsulated inside the open canalicular system of PLTs, and cytotoxic T lymphocytes (CTLs)‐responsive aPDL1 nanogels (NGs) are covalently backpacked on the PLT surface. Upon systemic administration, the pharmacytes enable prolonged blood circulation and active accumulation to tumors, wherein PLTs are activated to liberate siRab NCs, which efficiently transfect tumor cells, silence Rab27a, and inhibit exosome secretion. The immunosuppression is thus relieved, leading to the activation, proliferation, and tumoral infiltration of cytotoxic T cells, which trigger latent aPDL1 release. As such, the competitive aPDL1 exhaustion by PD‐L1‐expressing exosomes is minimized to sensitize ICB. Synergistically, siRab and aPDL1 induce strong antitumor immunological response and memory against syngeneic murine melanoma. This study reports a bioinspired mechanism to resolve the blood circulation/cell internalization contradiction of polycationic siRNA delivery systems, and renders an enlightened approach for the spatiotemporal enhancement of antitumor immunity.
The manipulation of the flexibility/rigidity of polymeric chains to control their function is commonly observed in natural macromolecules but largely unexplored in synthetic systems. Herein, we construct a series of protein-mimetic nano-switches consisting of a gold nanoparticle (GNP) core, a synthetic polypeptide linker, and an optically functional molecule (OFM), whose biological function can be dynamically regulated by the flexibility of the polypeptide linker. At the dormant state, the polypeptide adopts a flexible, random-coiled conformation, bringing GNP and OFM in close proximity that leads to the “turn-off” of the OFM. Once treated with alkaline phosphatase (ALP), the nano-switches are activated due to the increased separation distance between GNP and OFM driven by the coil-to-helix and flexible-to-rigid transition of the polypeptide linker. The nano-switches therefore enable selective fluorescence imaging or photodynamic therapy in response to ALP overproduced by tumor cells. The control over polymer flexibility represents an effective strategy to manipulate the optical activity of nano-switches, which mimics the delicate structure–property relationship of natural proteins.
Oral delivery of small interfering RNA (siRNA) provides a promising paradigm for treating diseases that require regular injections. However, the multiple gastrointestinal (GI) and systemic barriers often lead to inefficient oral absorption and low bioavailability of siRNA. Technologies that can overcome these barriers are still lacking, which hinders the clinical potential of orally delivered siRNA. Herein, small‐sized, fluorinated nanocapsules (F‐NCs) are developed to mediate efficient oral delivery of tumor necrosis factor α (TNF‐α) siRNA for anti‐inflammation treatment. The NCs possess a disulfide‐cross‐linked shell structure, thus featuring robust stability in the GI tract. Because of their small size (≈30 nm) and fluorocarbon‐assisted repelling of mucin adsorption, the best‐performing F3‐NCs show excellent mucus penetration and intestinal transport capabilities without impairing the intestinal tight junction, conferring the oral bioavailability of 20.4% in relative to intravenous injection. The disulfide cross‐linker can be cleaved inside target cells, causing NCs dissociation and siRNA release to potentiate the TNF‐α silencing efficiency. In murine models of acute and chronic inflammation, orally delivered F3‐NCs provoke efficient TNF‐α silencing and pronounced anti‐inflammatory efficacies. This study therefore provides a transformative strategy for oral siRNA delivery, and will render promising utilities for anti‐inflammation treatment.
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