Engineered Toll-like Receptor Nanoagonist Binding to Extracellular Matrix Elicits Safe and Robust Antitumor Immunity.
ACS Nano
; 17(6): 5340-5353, 2023 03 28.
Article
en En
| MEDLINE
| ID: mdl-36913671
ABSTRACT
Cancer immunotherapy, such as the Toll-like receptor (TLR) agonist including CpG oligodeoxynucleotide, has shown potency in clinical settings. However, it is still confronted with multiple challenges, which include the limited efficacy and severe adverse events caused by the rapid clearance and systemic diffusion of CpG. Here we report an improved CpG-based immunotherapy approach composed of a synthetic extracellular matrix (ECM)-anchored DNA/peptide hybrid nanoagonist (EaCpG) via (1) a tailor designed DNA template that encodes tetramer CpG and additional short DNA moieties, (2) generation of elongated multimeric CpG through rolling circle amplification (RCA), (3) self-assembly of densely packaged CpG particles composed of tandem CpG building blocks and magnesium pyrophosphate, and (4) incorporation of multiple copies of ECM binding peptide through hybridization to short DNA moieties. The structurally well-defined EaCpG shows dramatically increased intratumoral retention and marginal systemic dissemination through peritumoral administration, leading to potent antitumor immune response and subsequent tumor elimination, with minimal treatment-related toxicity. Combined with conventional standard-of-care therapies, peritumor administration of EaCpG generates systemic immune responses that lead to a curative abscopal effect on distant untreated tumors in multiple cancer models, which is superior to the unmodified CpG. Taken together, EaCpG provides a facile and generalizable strategy to simultaneously potentiate the potency and safety of CpG for combinational cancer immunotherapies.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias
Límite:
Animals
/
Humans
Idioma:
En
Revista:
ACS Nano
Año:
2023
Tipo del documento:
Article
País de afiliación:
China