Abstract
Intratumoral immunotherapy is an emerging modality for the treatment of solid tumors. Toll-like receptor (TLR) agonists have shown promise for eliciting immune responses, but systemic administration often results in the development of adverse side effects. Herein, we investigate whether localized delivery of the TLR agonist, resiquimod (R848), via platelet membrane-coated nanoparticles (PNP-R848) elicits antitumor responses. The membrane coating provides a means of enhancing interactions with the tumor microenvironment, thereby maximizing the activity of R848. Intratumoral administration of PNP-R848 strongly enhances local immune activation and leads to complete tumor regression in a colorectal tumor model, while providing protection against repeated tumor re-challenges. Moreover, treatment of an aggressive breast cancer model with intratumoral PNP-R848 delays tumor growth and inhibits lung metastasis. Our findings highlight the promise of locally delivering immunostimulatory payloads using biomimetic nanocarriers, which possess advantages such as enhanced biocompatibility and natural targeting affinities.
Highlights
Intratumoral immunotherapy is an emerging modality for the treatment of solid tumors
Upon binding of R848 to TLR7/8, multiple immunomodulatory cytokines, including interleukin 6 (IL-6), IL-12, and interferon α (IFNα) are released, triggering a cascade of signaling pathways that leads to the activation of antigen-presenting cells (APCs) and polarization of T cell responses[16,17,18]
Given the multitude of interactions of platelets with other cell types and tissues[39,40,41,42,43,44], we aimed to leverage these unique abilities to design a nanoparticle platform incorporating natural targeting abilities. This was done by directly coating the membrane isolated from human platelets through a differential centrifugation and freeze-thaw process onto biocompatible and biodegradable polylactic acid (PLA) nanoparticle cores via sonication[37], an energetically favorable process that promotes colloidal stabilization[45]
Summary
Intratumoral immunotherapy is an emerging modality for the treatment of solid tumors. Tolllike receptor (TLR) agonists have shown promise for eliciting immune responses, but systemic administration often results in the development of adverse side effects. The systemic administration of R848 and other members of the TLR7 agonist family in combination with checkpoint inhibitors has proven advantageous in the treatment of squamous cell carcinoma, colon carcinoma, metastatic melanoma, and pancreatic cancer[18,22,23,24], there are drawbacks limiting their clinical translation. Some reports suggested that systemic administration of R848 leads to rapid depletion of leukocytes and transient local immune insufficiency[29] To overcome these challenges, intratumoral injection of TLR7 agonists has been investigated as a more clinically relevant route of administration to address solid tumors[30,31,32,33,34]. In order for intratumoral immunotherapies to be effective, it is necessary to confine the immune agonist payloads within the tumor site
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