Guanidine-modified nanoparticles as robust BTZ delivery carriers and activators of immune responses.

Dendritic cells (DCs), the primary antigen-presenting cells in the immune system, play a critical role in regulating tumor immune responses. However, the tumor immunosuppressive microenvironment severely impedes the process of antigen-presenting and DC maturation, thereby limiting the efficacy of cancer immunotherapy. In this work, a pH-responsive polymer nanocarrier (PAG) modified with aminoguanidine (AG) was constructed for the efficient delivery of bortezomib (BTZ) through bidentate hydrogen bonds and electrostatic adsorption formed between guanidine groups of PAG and boronic acid groups of BTZ. The obtained PAG/BTZ nanoparticles exhibited pH-responsive release of BTZ and AG in the acidic tumor microenvironment. On the one hand, BTZ induced potent immune activation by eliciting immunogenic cell death (ICD) and releasing damage-associated molecular patterns. On the other hand, the cationic AG significantly promoted antigen uptake by DCs and activated DC maturation. As a result, PAG/BTZ significantly stimulated tumoral infiltration of cytotoxic T lymphocytes (CTLs) and triggered robust antitumor immune responses. Thus, it showed potent antitumor efficacy when synergizing with an immune checkpoint-blocking antibody. A pH-responsive aminoguanidine (AG)-modified nanoparticle (PAG/BTZ) for tumoral delivery of bortezomib (BTZ) was fabricated successfully to improve the chemo-immunotherapy efficacy by eliciting immunogenic cell death (ICD), promoting dendritic cells (DCs) maturation, and synergizing with an immune checkpoint-blocking antibody (α-PDL1). [Display omitted] • The PAG/BTZ nanoparticles induced strong tumor immunogenic cell death to increase the immunogenicity. • The PAG/BTZ nanoparticles improved chemo-immunotherapy efficacy by activating DCs and promoting their maturation. • The PAG/BTZ showed potent antitumor efficacy when synergizing with an immune checkpoint-blocking antibody (αPD-L1). [ABSTRACT FROM AUTHOR]