Immunotherapy shows promising therapeutic potential for long‐term tumor regression. However, current cancer immunotherapy displays a low response rate due to insufficient immunogenicity of the tumor cells. To address these challenges, herein, intracellular‐acidity‐activatable dynamic nanoparticles for eliciting immunogenicity by inducing ferroptosis of the tumor cells are engineered. The nanoparticles are engineered by integrating an ionizable block copolymer and acid‐liable phenylboronate ester (PBE) dynamic covalent bonds for tumor‐specific delivery of the ferroptosis inducer, a glutathione peroxidase 4 inhibitor RSL‐3. The nanoparticles can stably encapsulate RSL‐3 inside the hydrophobic core via π–π stacking interaction with the PBE groups at neutral pH (pH = 7.4), while releasing the payload in the endocytic vesicles (pH = 5.8–6.2) by acidity‐triggered cleavage of the PBE dynamic covalent bonds. Furthermore, the nanoparticles can perform acid‐activatable photodynamic therapy by protonation of the ionizable core, and significantly recruit tumor‐infiltrating T lymphocytes for interferon gamma secretion, and thus sensitize the tumor cells to RSL‐3‐inducible ferroptosis. The combination of nanoparticle‐induced ferroptosis and blockade of programmed death ligand 1 efficiently inhibits growth of B16‐F10 melanoma tumor and lung metastasis of 4T1 breast tumors, suggesting the promising potential of ferroptosis induction for promoting cancer immunotherapy.
PROteolysis TArgeting Chimeras (PROTACs) has been exploited to degrade putative protein targets. However, the antitumor performance of PROTACs is impaired by their insufficient tumour distribution. Herein, we present de novo designed polymeric PROTAC (POLY-PROTAC) nanotherapeutics for tumour-specific protein degradation. The POLY-PROTACs are engineered by covalently grafting small molecular PROTACs onto the backbone of an amphiphilic diblock copolymer via the disulfide bonds. The POLY-PROTACs self-assemble into micellar nanoparticles and sequentially respond to extracellular matrix metalloproteinase-2, intracellular acidic and reductive tumour microenvironment. The POLY-PROTAC NPs are further functionalized with azide groups for bioorthogonal click reaction-amplified PROTAC delivery to the tumour tissue. For proof-of-concept, we demonstrate that tumour-specific BRD4 degradation with the bioorthogonal POLY-PROTAC nanoplatform combine with photodynamic therapy efficiently regress tumour xenografts in a mouse model of MDA-MB-231 breast cancer. This study suggests the potential of the POLY-PROTACs for precise protein degradation and PROTAC-based cancer therapy.
Packaging multiple drugs into a nanocarrier with rational design to achieve synergistic cancer therapy remains a challenge due to the intrinsically varied pharmacodynamics of therapeutic agents. Especially difficult is combining small-molecule drugs and macromolecular biologics. Here, we successfully graft pheophorbide A (PPA) photosensitizers on DNA backbone at predesigned phosphorothioate modification sites. The synthesized four PPA-grafted DNAs are assembled into a tetrahedron framework, which further associates with a programmed death ligand-1 (PD-L1) small interfering RNA (siRNA) linker through supramolecular self-assembly to form an siRNA and PPA copackaged nanogel. With dual therapeutic agents inside, the nanogel can photodynamically kill tumor cells and induce remarkable immunogenic cell death. Also, it simultaneously silences the PD-L1 expression of the tumor cells, which substantially promotes the antitumor immune response and leads to an enhanced antitumor efficacy in a synergistic fashion.
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