Meng Guan

Cuproptosis is an emerging mode of programmed cell death for tumor suppression but sometimes gets resisted by tumor cells resist under specific mechanisms. Inhibiting copper transporter ATPase (ATP7A) was found to disrupt copper ion homeostasis, thereby enhancing the effect of cuproptosis and eventually inhibiting tumor invasion and metastasis. In this study, we develop a multifunctional nanoplatfrom based on Cu9S8 (CAPSH), designed to enhance cuproptosis in tumor cells by specifically targeting ATP7A interference, while combining thermodynamic therapy with immune effects. The release of copper ions from CAPSH and the copper homeostasis interference by siRNA cooperatively increases the concentration of copper ions in tumor cells, which induces effectively cuproptosis and activates immune responses for suppressing development and metastasis of tumor. This nanoplatform simultaneously regulates cuproptosis from both principles of onset and development, facilitating the application of cuproptosis in tumor therapy. Cuproptosis is an emerging mode of programmed cell death for tumor suppression but limited by the copper ion regulatory mechanisms in most tumor cells. Here, this group develops a Cu9S8-based nanoplatform for breast cancer-targeting and cuproptosis-induction via ATP7A interference, thereby eliciting thermodynamic cancer therapy.

Tumor immune checkpoint therapy (ICT) aims to block immune escape signals between tumor and immune cells. However, low delivery efficiency of immune checkpoint inhibitors (ICIs), narrow single-target approach, and reduced responsiveness notably hinder clinical development of ICT. Here, we developed a nanoliposome-bacteria hybrid system that acts as an antibody (Ab) factory, enabling precise tumor targeting and macrophage activation in hypoxic environments. We reprogrammed attenuated Escherichia coli MG1655 to synthesize CD47 antibodies (aCD47) in response to hypoxic tumor microenvironments while surface conjugating with redox-responsive macrophage colony-stimulating factor-loaded liposomes. This system leverages bacterial tropism to enhance macrophage infiltration and polarization. The low oxygen levels trigger in situ aCD47 expression, blocking the “do not eat me” signal and boosting macrophage antitumor activity. In addition, macrophage antigen presentation activates CD8+CD3+ T cells, amplifying systemic antitumor immunity. Analysis of the gut microbiome shows reduced pathogenicity and improved intestinal tolerance with increased probiotics.

In clinical practice, surgical removal of tumors often leaves behind small tumors and circulating tumor cells, increasing the risk of metastasis and recurrence, which seriously affects treatment outcomes. Immunotherapy activates the immune system to monitor and inhibit tumor metastasis and recurrence long-term. However, inflammatory microenvironments at surgical sites lead to immunosuppressive tumor-associated macrophages (TAMs), causing immune evasion. Additionally, tumor cells overexpress the immune checkpoint CD47, further weakening the phagocytic and cytotoxic functions of macrophages. Here, the bacterial outer membrane vesicles (OMV) hitchhiking on neutrophils are utilized to precisely deliver immune checkpoint blockade antibodies to the tumor resection site. Escherichia coli is reprogrammed to express CD47 antibody and used to extract CD47 antibody-containing OMV, followed by insertion of Ce6 photosensitizer into the membrane (OC47-Ce6). Purified autologous neutrophils phagocytose and carry OC47-Ce6 for precise targeting to the postoperative tumor resection site, mediating tumor cell killing, aCD47 release, and tumor-associated antigen presentation by light. In vitro and in vivo experiments demonstrate that OC47-Ce6 enhances TAM phagocytic function through TAM polarization and CD47 blockade. This approach effectively activates T-cell anti-tumor immune responses and significantly reduces the risk of postoperative tumor recurrence and metastasis.

Abstract As a promising gene therapy strategy, controllable small molecule‐mRNA covalent modification in tumor cells could be initiated by singlet oxygen ( 1 O 2 ) to complete the modification process. However, in vivo generation of 1 O 2 is usually dependent on excitation of external light, and the limited light penetration of tissues greatly interferes the development of deep tumor photo therapy. Here, we constructed a tumor‐targeting nano‐micelle for the spontaneous intracellular generation of 1 O 2 without the need for external light, and inducing a high level of covalent modification of mRNA in tumor cells. Luminol and Ce6 were chemically bonded to produce 1 O 2 by chemiluminescence resonance energy transfer (CRET) triggered by high levels of hydrogen peroxide (H 2 O 2 ) in the tumor microenvironment (TME). The sufficient 1 O 2 oxidized the loaded furan to highly reactive dicarbonyl moiety, which underwent cycloaddition reaction with adenine (A), cytosine (C) or guanine (G) on the mRNA for interfering with the tumor cell protein expression, thereby inhibiting tumor progression. In vitro and in vivo experiments demonstrated that this self‐initiated gene therapy nano‐micelle could induce covalent modification of mRNA by 1 O 2 without external light, and the process could be monitored in real time by fluorescence imaging, which provided an effective strategy for RNA‐based tumor gene therapy.

Mitochondria-targeting photothermal therapy could significantly enhance the tumor cell killing effect. However, since therapeutic reagents need to overcome a series of physiological obstacles to arrive at mitochondria accurately, precise mitochondria-targeting photothermal therapy still faces great challenges. In this study, we developed a self-delivery nanoplatform that specifically targeted the mitochondria of tumor cells for precise photothermal therapy. Photothermal agent IR780 was encapsulated by amphiphilic apoptotic peptide KLA with mitochondria-targeting ability to form nanomicelle KI by self-assembly through hydrophilic and hydrophobic interactions. Subsequently, negatively charged tumor-targeting polymer HA was coated on the surface of KI through electrostatic interactions, to obtain tumor mitochondria-targeting self-delivery nanoplatform HKI. Through CD44 receptor-mediated recognition, HKI was internalizated by tumor cells and then disassembled in an acidic environment with hyaluronidase in endosomes, resulting in the release of apoptotic peptide KLA and photothermal agent IR780 with mitochondria anchoring capacity, which achieved precise mitochondria guidance and destruction. This tumor mitochondria-targeting self-delivery nanoplatform was able to effectively deliver photothermal agents and apoptotic peptides to tumor cell mitochondria, resulting in precise destruction to mitochondria and enhancing tumor cell inhibition at the subcellular organelle level.