Background: Photodynamic therapy (PDT) has emerged as a promising strategy for oral cancer treatment. Verteporfin is a powerful photosensitizer and widely used in the treatment of macular degeneration. However, rare work has reported its potential in the treatment of oral cancer. Methods: In this study, we introduce an innovative approach of nano-photosensitizer based on Verteporfin, which was prepared by utilizing macrophage membrane to coat Verteporfin-loaded zeolitic imidazolate framework 8 (ZIF-8) for effective photodynamic therapy against oral cancer. Nanoparticle characteristics were assessed including size, zeta potential, and PDI. Cellular uptake studies were conducted using CAL-27 cells. Furthermore, inhibitory effects in both in vitro and in vivo settings were observed, ensuring biosafety. Assessment of anticancer efficacy involved tumor volume measurement, histological analyses, and immunohistochemical staining. Results: In vitro experiments indicated that the nano-photosensitizer showed efficient cellular uptake in the oral cancer cells. Upon the laser irradiation, the nano-photosensitizer induced the generation of reactive oxygen species (ROS), leading to cancer cell apoptosis. The in vivo experiments indicated that the coating with cell membranes enhanced the circulation time of nano-photosensitizer. Moreover, the specificity of the nano-photosensitizer to the cancer cells was also improved by the cell membrane-camouflaged structure in the tumor-bearing mouse model, which inhibited the tumor growth significantly by the photodynamic effect in the presence of laser irradiation. Conclusion: Overall, our findings demonstrate the potential of macrophage membrane-coated ZIF-8-based nanoparticles loaded with Verteporfin for effective photodynamic therapy in oral cancer treatment. This nano-system holds promise for synergistic cancer therapy by combining the cytotoxic effects of PDT with the activation of the immune system, providing a novel therapeutic strategy for combating cancer.

Periodontitis is the most prevalent oral disease worldwide, leading to inflammation, alveolar bone loss, and tooth loss. Mesenchymal stem cells (MSCs) transplantation has the potential to alleviate periodontitis and restore alveolar bone, but numerous studies have found that transplanted MSCs undergo apoptosis, releasing apoptotic extracellular vesicles (ApoEVs). Human periodontal ligament stem cells (hPDLSCs) ApoEVs have immunomodulatory and tissue regenerative potential. Still, their role in periodontitis treatment and alveolar bone restoration has not been investigated yet. The study isolated hPDLSCs-ApoEVs and investigated the modulatory effect on macrophaghe. We explored the specific molecular mechanisms of hPDLSC-ApoEVs in regulating macrophage polarization in vitro through mRNA-seq and inhibitors. Co-culture experiment demonstrated that hPDLSC-ApoEVs promoted hPDLSC osteogenic differentiation by regulating macrophage polarization. Finally, we verified that hPDLSC-ApoEVs inhibited periodontitis-induced periodontal tissue defects and promoted periodontal bone tissue regeneration in vivo. This study found that hPDLSCs-ApoEVs regulate M0 to anti-inflammatory M2 macrophage polarization, as indicated by the upregulation of CD163, IL-10, and ARG1. hPDLSCs-ApoEVs activated NF-κB signaling that upregulated S100A9 in macrophages. hPDLSCs-ApoEVs failed M2 macrophage polarization during inhibition of NF-κB or S100A9. Furthermore, hPDLSCs-ApoEVs-treated macrophage-conditioned medium robustly promoted osteogenic differentiation of hPDLSCs in vitro. Finally, we verified these results in the periodontitis model of male C57BL/6 mice. Local injection of hPDLSCs-ApoEVs facilitated macrophage M2 polarization, alleviated periodontitis, and restored alveolar bone. In conclusion, these findings provide new evidence for the clinical application of hPDLSCs-ApoEVs in periodontitis treatment via macrophage immune modulation-mediated alveolar bone restoration.

Background: The photodynamic therapy (PDT) showed promising potential in treating tongue squamous cell carcinoma (TSCC). The Food and Drug Administration approved Verteporfin (Ver) is a powerful alternative in this field for its penetrating power and high production of reactive oxygen species (ROS). However, its applications in the treatment of TSCC are still rare. Methods: Ver was loaded onto Poly (lactic-co-glycolic acid) (PLGA) nanoparticles, followed by the modification with RGD peptide as the ligand. The nanostructured was named as RPV. In vitro assessments were conducted to evaluate the cytotoxicity of RPV through the Live/Dead assay analysis and Cell Counting Kit-8 (CCK-8) assay. Using the reactive oxygen species assay kit, the potential for inducing targeted tumor cell death upon laser irradiation by promoting ROS production was investigated. In vivo experiments involved with the biological distribution of RPV, the administration with RPV followed by laser irradiation, and the measurement of the tumor volumes. Immunohistochemical analysis was used to detect the Ki-67 expression, and apoptosis induced by RPV-treated group. Systemic toxicity was evaluated through hematoxylin-eosin staining and blood routine analysis. Real-time monitoring was employed to track RPV accumulation at tumor sites. Results: The in vitro assessments demonstrated the low cytotoxicity of RPV and indicated its potential for targeted killing TSCC cells under laser irradiation. In vivo experiments revealed significant tumor growth inhibition with RPV treatment and laser irradiation. Immunohistochemical analysis showed a notable decrease in Ki-67 expression, suggesting the effective suppression of cell proliferation, and TUNEL assay indicated the increased apoptosis in the RPV-treated group. Pathological examination and blood routine analysis revealed no significant systemic toxicity. Real-time monitoring exhibited selective accumulation of RPV at tumor sites. Conclusion: The findings collectively suggest that RPV holds promise as a safe and effective therapeutic strategy for TSCC, offering a combination of targeted drug delivery with photodynamic therapy.

Gene therapy has emerged as a potential approach for lung cancer therapy. However, the application of gene therapy is still limited by their properties, such as low specificity to the cancer cells, negatively charged groups, short systemic circulation time, and rapid degradation by nucleases. The progression of lung adenocarcinoma (LUAD) can be promoted through the methylation process of miR‐148a‐3p promoter, as confirmed by our previous research. In the current study, we are the first to design a mirrored Arg‐Gly‐Asp (RGD)‐modified cationic peptide (RD24) as a microRNA (miRNA) vehicle, which enabled to pack the miRNA (miR‐148a‐3p) efficiently and generate RD24/miR‐148a‐3p nanoparticles (RPRIN) by self‐assembling. RPRIN exhibited a high transfection efficiency in lung cancer cells via the conjugation between RGD and integrins on the surface of lung cancer cells. Furthermore, RD24 showed matrix metallopeptidase 2 (MMP2) responsiveness, which improved lung cancer cell inhibition induced by the miRNA intracellularly. In addition, RPRIN exhibits several advantages, such as prolonged circulation duration, reduced toxicity, and immune escape. Experiments conducted both in vitro and in vivo revealed that RPRIN effectively suppressed the growth and progression of lung cancer. Thus, the mirrored RGD‐modified cationic peptide showed great potential in transducing miRNA for lung cancer therapy.

Background: Tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) typically polarize toward an M2 phenotype that promotes tumor progression and immune suppression. Reprogramming TAMs to the proinflammatory M1 phenotype has emerged as a promising strategy to boost antitumor immunity. This study aimed to develop a targeted nanoplatform to deliver small activating RNAs (saRNAs) that upregulate genes involved in macrophage reprogramming. Results: We designed saRNAs targeting the promoters of p38 and TFEB, encapsulated within a metal-organic framework (MOF)-based delivery system and cloaked with hybrid membranes composed of synthetic lipids and exosome-derived vesicles. These were further functionalized with the TAM-targeting peptide CRV (CRVLRSGSC), resulting in nanoparticles termed CLMSR. CLMSR selectively accumulated in macrophages, enhancing intracellular saRNA delivery. Functional assays revealed that conditioned medium from CLMSR-treated M2 macrophages suppressed tumor cell migration, invasion, and 3D spheroid formation. In vivo, CLMSR demonstrated prolonged circulation time and enhanced tumor targeting. Importantly, treatment remodeled the TME by increasing CD8⁺ and CD4⁺ T cell infiltration and promoting TAM repolarization from the M2 to M1 phenotype. Conclusions: Our findings demonstrate that CLMSR represents a novel and efficient nanoplatform for saRNA delivery to reprogram TAMs and modulate the TME. By targeting M2 macrophages and inducing their transition to the tumoricidal M1 phenotype, this approach offers a promising therapeutic avenue to enhance antitumor immunity and inhibit tumor progression.