Dechun Liu

Cuproptosis, a newly identified form of copper-dependent programmed cell death, has emerged as a potential therapeutic strategy for cancer treatment. However, its antitumor efficacy was strictly limited by dysregulated glycolytic metabolism of tumor cells. Herein, we proposed multifunctional copper-based nano-PROTACs (CHNDs) to degrade hexokinase 2 (HK-2) and amplify cuproptosis for cancer therapy via dual mitochondrial energy depletion. Our initial evaluation indicated that polyethyleneimine (PEI)-based nano-PROTACs (PHDs) triggered HK-2 degradation via the ubiquitin–proteasome system (UPS). PHDs reduced HK-2 expression to 43.7% in 4T1 cells and 42.1% in CT26 cells, which consequently impaired glycolysis in tumor cells. Furthermore, copper ion release from CHNDs in a controlled manner and the glucose metabolism homeostasis interference by PHDs orchestrally induced effective cuproptosis and glycolysis inhibition for suppressing development and metastasis of tumor cells. Notably, CHNDs markedly inhibited the growth of murine colon and breast tumors by simultaneously disrupting mitochondrial respiration and glycolysis, resulting in tumor inhibition rates of 76.6% and 55.3%, respectively, and extending the median survival of CT26 tumor-bearing mice from 21 to 29 d. Our designed multifunctional engineered nanoparticle-based targeted protein degraders facilitated a new paradigm for precise oncology and proteolysis-targeting chimera (PROTAC) development.

Biomacromolecules in physiological environments would adsorb onto the nanoparticles (NPs) to form corona layers, in which protein coronas (PCs) are the major constituent. PCs always play diverse influences on the fate of NPs in vitro and in vivo, especially for active-targeting NPs (e.g., transferrin-modified nanoparticles, Tf-NP). In order to eliminate the inhibition of PCs on the efficiency of Tf-NP, the precoated Tf-NP with bovine serum albumin (BSA, B@Tf-NP) was designed to fabricate an "active PCs" (PCs formed by artificial modification) against the "passive PCs" (PCs formed in the biological environments), which was inspired by the formation pattern of PCs. The results indicated that B@Tf-NP had similar particle size, dispersion, and physical stability with Tf-NP. Surprisingly, B@Tf-NP enhanced the cellular uptake in enterocytes and permeability in intestinal tract of mice. Notably, the concentration ratio of BSA to Tf that could ensure Tf revealed timely during the interacted process was considered to be appropriate. These findings provide an easy while efficient design platform for active-targeting NPs to overcome the biomacromolecular barrier in oral administration.

The epithelial mucosa is a key biological barrier faced by gastrointestinal, intraoral, intranasal, ocular, and vaginal drug delivery. Ligand-modified nanoparticles demonstrate excellent ability on this process, but their efficacy is diminished by the formation of protein coronas (PCs) when they interact with biological matrices. PCs are broadly implicated in affecting the fate of NPs in vivo and in vitro, yet few studies have investigated PCs formed during interactions of NPs with the epithelial mucosa, especially mucus. In this study, we constructed transferrin modified NPs (Tf-NPs) as a model and explored the mechanisms and effects that epithelial mucosa had on PCs formation and the subsequent impact on the transcellular transport of Tf-NPs. In mucus-secreting cells, Tf-NPs adsorbed more proteins from the mucus layers, which masked, displaced, and dampened the active targeting effects of Tf-NPs, thereby weakening endocytosis and transcellular transport efficiencies. In mucus-free cells, Tf-NPs adsorbed more proteins during intracellular trafficking, which enhanced transcytosis related functions. Inspired by soft coronas and artificial biomimetic membranes, we used mucin as an "active PC" to precoat Tf-NPs (M@Tf-NPs), which limited the negative impacts of "passive PCs" formed during interface with the epithelial mucosa and improved favorable routes of endocytosis. M@Tf-NPs adsorbed more proteins associated with endoplasmic reticulum-Golgi functions, prompting enhanced intracellular transport and exocytosis. In summary, mucus shielded against the absorption of Tf-NPs, but also could be employed as a spear to break through the epithelial mucosa barrier. These findings offer a theoretical foundation and design platform to enhance the efficiency of oral-administered nanomedicines.

Cancer immunotherapy is expected to achieve tumor treatment mainly by stimulating the patient's own immune system to kill tumor cells. However, the low immunogenicity of the tumor and the poor efficiency of tumor antigen presentation result in a variety of solid tumors that do not respond to immunotherapy. Herein, we designed a proton-gradient-driven porphyrin-based liposome (PBL) with highly efficient Toll-like receptor 7 (TLR7) agonist (imiquimod, R837) encapsulation (R837@PBL). R837@PBL rapidly released R837 in the acid microenvironment to activate the TLR in the endosome inner membrane to promote bone-marrow-derived dendritic cell maturation and enhance antigen presentation. R837@PBL upon laser irradiation triggered immunogenic cell death of tumor cells and tumor-associated antigen release after subcutaneous injection, activated TLR7, formed in situ tumor nanoadjuvants, and enhanced the antigen presentation efficiency. Photoimmunotherapy promoted the infiltration of cytotoxic T lymphocytes into tumor tissues, inhibited the growth of the treated and abscopal tumors, and exerted highly effective photoimmunotherapeutic effects. Hence, our designed in situ tumor nanoadjuvants are expected to be an effective treatment for treated and abscopal tumors, providing a novel approach for synergistic photoimmunotherapy of tumors.

Cancer immunotherapy, such as immune checkpoint blockade, chimeric antigen receptor, and cytokine therapy, has emerged as a robust therapeutic strategy activating the host immune system to inhibit primary and metastatic lesions. However, low tumor immunogenicity (LTI) and immunosuppressive tumor microenvironment (ITM) severely compromise the killing effect of immune cells on tumor cells, which fail to evoke a strong and effective immune response. As an exogenous stimulation therapy, phototherapy can induce immunogenic cell death (ICD), enhancing the therapeutic effect of tumor immunotherapy. However, the lack of tumor targeting and the occurrence of immune escape significantly reduce its efficacy in vivo, thus limiting its clinical application. Nanophotoimmunotherapy (nano-PIT) is a precision-targeted tumor treatment that co-loaded phototherapeutic agents and various immunotherapeutic agents by specifically targeted nanoparticles (NPs) to improve the effectiveness of phototherapy, reduce its phototoxicity, enhance tumor immunogenicity, and reverse the ITM. This review will focus on the theme of nano-PIT, introduce the current research status of nano-PIT on converting "cold" tumors to "hot" tumors to improve immune efficacy according to the classification of immunotherapy targets, and discuss the challenges, opportunities, and prospects.