Targeted protein degradation technologies—particularly proteolysis-targeting chimeras (PROTACs)—have recently emerged as powerful tools in cancer therapy. However, it remains unclear whether tumor cells can mount immediate responses to proteolysis, potentially leading to acquired resistance and diminished therapeutic efficacy. This critical knowledge gap prompted us to investigate the underlying mechanisms and to develop preventive strategies. Here, we synthesized a PROTAC molecule targeting anaplastic lymphoma kinase–rearranged non-small cell lung cancer (ALK + NSCLC), termed ALK-PROTAC (AP). We confirmed the presence of immediate adaptive resistance responses following AP withdrawal, characterized by rapid re-expression of ALK and accelerated cellular proliferation. Mechanistically, these adaptive responses were driven by a cascade of metabolic remodeling events, including enhanced glucose and purine metabolism, along with upregulation of genes associated with reactive oxygen species (ROS) and hypoxia responses. These processes were closely linked to mitochondrial function, thereby increasing energy production in ALK + NSCLC cells after AP withdrawal, upregulating mitochondrial anti-apoptotic proteins, and enhancing the transcriptional activity of Yes-associated protein 1 (YAP1). To overcome this resistance, we leveraged the metabolism-disrupting properties of bisphosphonates, specifically alendronate sodium (Aln), which induces mitochondrial dysfunction and metabolic perturbation via inhibition of the mevalonate pathway. We subsequently developed alendronate-calcium coordination nanoparticles encapsulating AP (Aln–AP NPs). As anticipated, Aln–AP NPs disrupted metabolic profiles, induced mitochondrial dysfunction, and abrogated AP-induced upregulation of anti-apoptotic proteins and YAP1. This intervention significantly delayed ALK re-expression and improved therapeutic outcomes both in vitro and in vivo . Collectively, these findings support metabolic intervention as an effective strategy to counteract immediate resistance to PROTAC-mediated proteolysis, addressing a key challenge in the field, expanding the scope of targeted protein degradation, and offering a novel approach to optimizing therapeutic efficacy.
As air pollution intensifies and the use of electronic devices proliferates, the incidence of dry eye (DE) has surged, posing a significant burden on visual health. Given its complex pathogenesis and multifaceted etiology, achieving optimal therapeutic outcomes through a single treatment approach remains elusive. Hydrogel-based drug delivery systems have garnered considerable research attention. Here, a photocurable hydrogel (CsA@F127DA/DA-PEG-GelMA), that possesses both anti-inflammatory and antioxidant properties and utilizes advanced multi-crosslinking technology, was developed. This novel formulation significantly enhances the delivery efficiency of the hydrophobic immunosuppressant cyclosporine A (CsA). Furthermore, the incorporation of dopamine (DA) not only provides potent antioxidant and, ROS-scavenging capabilities, addressing ocular surface inflammatory disorders, but also endows the multifunctional hydrogel system with exceptional adhesion properties. The results showed that CsA@F127DA/DA-PEG-GelMA could not only inhibit the activation of NF-κB signaling pathway, regulate the polarization of macrophages and inhibit conjunctival inflammatory infiltration, but also inhibited the activation of HIF-1α signaling pathway, regulated glucose metabolism reprogramming, reduced the production of ROS, and thus maintained mitochondrial redox homeostasis. In summary, the dual inhibitory effect of CsA@F127DA/DA-PEG-GelMA on inflammation and oxidative stress effectively ameliorated the vicious cycle of DE, increased tear secretion, and significantly alleviated DE symptoms.
Conventional vascular disrupting agent (VDA) therapy is limited by off-target toxicity and an inability to exploit high permeability, thus constraining self-enhancing drug delivery. Moreover, the immunosuppressive macrophages recruited by VDAs further diminish therapeutic efficacy. In this work, we develop an Endoglin-targeted Nano-Framework to Obtain Repolarized Cancer-associated macrophages and Enhanced permeability (designated ENFORCE) for breast cancer immunotherapy. ENFORCE incorporates an endoglin-targeting peptide for precise binding to tumor vasculature and co-delivers the vascular disrupting agent combretastatin A4 (CA4) together with the immunomodulator R848. Upon release, CA4 rapidly disrupts tumor vasculature, thereby amplifying the enhanced permeability and retention (EPR) effect and promoting subsequent ENFORCE accumulation. Concurrently, CA4-induced recruitment of immunosuppressive macrophages is counteracted by R848, which reprograms tumor-associated macrophages toward a pro-inflammatory M1 phenotype. This combination of vascular remodeling and immune reprogramming enhances the tumor retention and bioavailability of αCD47, thereby boosting systemic antitumor immunity and eradicating metastatic tumors without causing obvious systemic toxicity. Overall, this work establishes a promising targeted nano-framework that integrates vascular disruption with macrophage immunomodulation, concurrently enhancing drug delivery and potentiating antitumor immunotherapy.
Lung cancer remains one of the leading causes of cancer-related mortality worldwide. Although nanomaterial-based cancer immunotherapy offers advantages such as efficient tumor targeting and flexible formulation design, its therapeutic efficacy is constrained by the low delivery efficiency of intravenous administration and the immunosuppressive tumor microenvironment. To overcome these delivery and immunological barriers, this study developed an inhalable, multitargeted biomimetic nanovaccine to enhance STING-mediated local antitumor immunity. The nanoparticles were fabricated by fusing tumor cell membranes with high calreticulin expression with liposomes co-loaded with the adjuvant monophosphoryl lipid A (MPLA) and 7-ethyl-10-hydroxycamptothecin (SN38). Pulmonary inhalation enabled dual-targeted delivery to dendritic cells and lung tumor cells, resulting in a 3.6-fold increase in tumor accumulation compared with that of uncoated nanoparticles. SN38 induced immunogenic cell death (ICD) and promoted the release of ICD-associated damage-associated molecular patterns, thereby facilitating activation of the cGAS-STING pathway, while MPLA further amplified the antitumor immune response. In vivo, the nanovaccine effectively suppressed tumor growth in orthotopic LLC models and reduced the number of metastatic nodules by approximately 86.7% in B16F10 lung metastasis models. Collectively, this study presents an inhalable biomimetic nanovaccine that integrates localized chemotherapy with in situ immune activation, thereby achieving potent therapeutic control of both primary and metastatic lung cancer.
