Slimming and Reinvigorating Tumor‐Associated Dendritic Cells with Hierarchical Lipid Rewiring Nanoparticles

Abstract

Dendritic cells (DCs) are crucial mediators of innate and adaptive antitumor immunity, whereas exogenously and endogenously driven lipid accumulation causes immune tolerance of tumor‐associated DCs (TADCs) and thereby diminishes tumor responsiveness to various therapies. Herein, a type of multilevel lipid rewiring nanoparticles (NPs) for TADC revitalization is designed. These self‐assembled NPs specifically bind to the lipid transport receptor Msr1 on the TADC surface and orchestrate the restriction of extracellular lipid uptake, cytoplasmic de novo lipid biosynthesis and nuclear lipogenic gene transcription. It is found that the slimming of TADCs via the three‐in‐one lipid metabolic reprogramming substantially promotes their maturation and rehabilitate their functions in inflammatory cytokine production, cytotoxic T cell recruitment, and tumor inhibition. Significantly, tumor resistance to immune checkpoint blockade therapy is further overcome. The study presents a non‐canonical strategy to remodel tumor‐infiltrating immune cells and paves a new path for improving the efficacy of cancer immunotherapy.

Unzippable Siamese Nanoparticles for Programmed Two‐Stage Cancer Immunotherapy

“…Monotherapy (𝛼PD-1 or SIANPs) or combination therapy (SIANPs + 𝛼PD-1) was administered in the mice bearing 4T1 tumors, which were well-established for their ICB resistance (Figure 6a). [8,40,41] Compared to the mock treatment, the 𝛼PD-1 treatment did not show any improvement on DC maturation. In contrast, SIANP-mediated upregulation in the levels of CD40 and MHC-II on the DC surface was strengthened via the combination with 𝛼PD-1 (Figure 6b,c; Figure S54, Supporting Information).…”

“…Nanoparticle (NP)-based carriers have paved the way for cellspecific drug delivery, whereas the demands for delivering therapeutic agents separately toward different cell types are increasing in cancer combination therapy. [38][39][40][41][42][43][44] Herein, we develop a type of non-covalently linked and ATP-responsive Siamese NPs (SIANPs), composed of tumor cell-targeting NPs, MDSCtargeting NPs, and ATP aptamer-incorporated interparticle DNA strands. These two kinds of NPs attach to each other via the hybridization of surface-decorated complementary singlestranded DNA (ssDNA) sequences and disconnect in responding to high levels of extracellular ATP in the TME.…”

Engineered biological nanoparticles as nanotherapeutics for tumor immunomodulation

“…Lipid rewiring nanoparticles and blockage of lipid uptake using composite hydrogels have demonstrated the reactivation of immune cells and inhibition of immunosuppressive immune cells. 302,303 Artificial antigen-presenting cells. Synthetic artificial antigen-presenting cells were formulated for T-cell activation.…”

Advancement of regulating cellular signaling pathways in NSCLC target therapy via nanodrug

“…At present, the pharmacokinetic behaviors of more nanodrugs are unclear, which is also an important reason for the low success rate of clinical transformation ( Cao and Chen, 2022 ). Multidisciplinary intersection brings the advantage of solving these problems, and therefore the exchange of new technologies among various disciplines needs to be enhanced ( Boehnke et al, 2022 ; Xu C. et al, 2023 ). Besides, studies on the regulation of signaling pathways by nanodrugs are mostly conducted in vitro or in animal models.…”