Platelet Pharmacytes for the Hierarchical Amplification of Antitumor Immunity in Response to Self‐Generated Immune Signals

Abstract

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.

Regulation of Extracellular Vesicle-Mediated Immune Responses against Antigen-Specific Presentation

“…Additionally, for the antagonism of CD47, a “Not Eat Me” signal is overexpressed on the surface of most tumours by a signal-regulatory protein alpha. This protein is expressed on phagocytic cells that interact with CD47-bearing EVs, inhibiting CD47 on cancer cells and thereby increasing cancer cell phagocytosis and inducing anti-tumour T cell responses [ 346 , 347 , 348 , 349 ]. Additionally, EVs have been shown to evade immune clearance better than artificial liposomes, likely due to the expression of CD47 on exosomal membranes.…”

“…siRNA-loaded exosomes are selectively taken up by pancreatic tumour cells, which is facilitated by enhanced micropinocytosis. This reduces oncogenic KRAS signalling and suppresses tumour growth in multiple mouse models of pancreatic cancer [ 349 ]. Therefore, increasing cancer cell phagocytosis by antagonising CD47 signalling with EVs may be an effective approach for cancer immunotherapy.…”

Organism‐Generated Biological Vesicles In Situ: An Emerging Drug Delivery Strategy

“…Subsequently, they further combined this strategy with thermal ablation to achieve remarkably diminished or even cleared tumor recurrence and metastasis. [ 47 ] Except for the insertion or conjugation method for the loading of free drug, drug‐loaded nanoparticles could also be integrated into platelets, including nanocomplex, [ 48 ] nanogels, nanodiamond, [ 49 ] and liposome. [ 50 ]…”

Cardiomyocyte-targeted anti-inflammatory nanotherapeutics against myocardial ischemia reperfusion (IR) injury

“…Because Te has weaker electronegativity than Se and Te-Te also has much lower bond energy (126 kJ/mol) than Se-Se (172 kJ/mol), ditellurium-containing polymers should have higher sensitivity to ROS [39][40][41]. Besides the dilemma associated with siRNA encapsulation and release, the polycation/siRNA NCs with positive surface charges are instable during blood circulation, because the negatively charged serum proteins will adsorb onto the NCs surface and ultimately cause the NCs clearance by reticuloendothelial tissues [42][43][44][45]. As such, it is highly imperative to develop serum-stable, cardiomyocyte-targeted NCs that can intracellularly liberate the siRNA cargo in response to the endogenous ROS level inside inflamed cardiomyocytes.…”