# Nanoencapsulated senotherapeutic compounds targeting connexin-43 for enhanced wound healing **Authors:** Marina Rodríguez-Candela Mateos, Jenifer García-Fernández, Sofia M. Saraiva, Maria Aurora Grimaudo, Sandra Alijas, Adela Escudero, Marta Varela-Eirín, Juan Pérez Cano, Benigno Acea Nebril, Luis C. Barrio, María D. Mayan, María de la Fuente PMC · DOI: 10.1016/j.isci.2025.114547 · iScience · 2025-12-26 ## TL;DR This study explores using nanoencapsulated drugs to target connexin-43 and improve wound healing in cancer patients. ## Contribution A novel nanoformulation combining oleuropein and BIRB796 is developed to enhance wound healing by targeting connexin-43. ## Key findings - Cx43 overexpression correlates with reduced gap junction communication and delayed healing. - Oleuropein restores fibroblast function and reduces senescence in cancer patient fibroblasts. - Nano-coencapsulated OLP+BIRB796 improves drug delivery and wound-healing efficacy. ## Abstract Oncological patients receiving radiotherapy or chemotherapy often experience impaired wound healing due to tissue damage and cellular senescence. Connexin43 (Cx43) is a key regulator in this process, promoting senescence and the SASP, which hinder regeneration. This study investigates targeting Cx43 in primary dermal fibroblasts from cancer patients using a new combination of nanoencapsulated drugs. We show that Cx43 overexpression correlates with reduced gap junction communication, increased senescence, and delayed healing. Treatment with oleuropein (OLP), a polyphenol with antioxidant and regenerative properties, restores fibroblast function, reduces senescence, and improves healing. We also examine the p38 MAPK inhibitor BIRB796, alone and with OLP, demonstrating its ability to suppress SASP and support tissue repair. After confirming the superior combined effect of OLP and BIRB796, we developed a co-encapsulated nanoformulation. This innovative approach may significantly enhance wound healing in oncological patients. •Cx43 alterations impairs healing by promoting senescence in cancer patient skin fibroblasts•Oleuropein restores fibroblast function and reduces cellular senescence•BIRB796 reduces SASP in senescent cancer patient fibroblasts, promoting regenerative repair•Nano-coencapsulated OLP+BIRB796 enhances delivery and wound-healing efficacy Cx43 alterations impairs healing by promoting senescence in cancer patient skin fibroblasts Oleuropein restores fibroblast function and reduces cellular senescence BIRB796 reduces SASP in senescent cancer patient fibroblasts, promoting regenerative repair Nano-coencapsulated OLP+BIRB796 enhances delivery and wound-healing efficacy Biological sciences; engineering; materials science ## Linked entities - **Genes:** GJA1 (gap junction protein alpha 1) [NCBI Gene 2697] - **Proteins:** CONNEXIN 43 (CONNEXIN 43 protein), ASPRV1 (aspartic peptidase retroviral like 1), P38mapk (p38 map kinase) - **Chemicals:** oleuropein (PubChem CID 5281544), BIRB796 (PubChem CID 156422) ## Full-text entities - **Genes:** Gja1 (gap junction protein, alpha 1) [NCBI Gene 14609] {aka Cnx43, Cx43, Cx43alpha1, Cxnk1, Gja-1, Npm1}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, MMP9 (matrix metallopeptidase 9) [NCBI Gene 4318] {aka CLG4B, GELB, MANDP2, MMP-9}, GLB1 (galactosidase beta 1) [NCBI Gene 2720] {aka EBP, ELNR1, MPS4B}, ASPRV1 (aspartic peptidase retroviral like 1) [NCBI Gene 151516] {aka ADLI, MUNO, SASP, SASPase, Taps}, MMP3 (matrix metallopeptidase 3) [NCBI Gene 4314] {aka CHDS6, MMP-3, SL-1, STMY, STMY1, STR1}, HPRT1 (hypoxanthine phosphoribosyltransferase 1) [NCBI Gene 3251] {aka HGPRT, HPRT}, Gja3 (gap junction protein, alpha 3) [NCBI Gene 14611] {aka Cnx46, Cx43, Cx46, Cxnj1, Gja-3}, Act1 (actin related gene 1) [NCBI Gene 109776] {aka Act-1}, MMP13 (matrix metallopeptidase 13) [NCBI Gene 4322] {aka CLG3, MANDP1, MDST, MMP-13}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, ERBB2 (erb-b2 receptor tyrosine kinase 2) [NCBI Gene 2064] {aka CD340, HER-2, HER-2/neu, HER2, MLN 19, MLN-19}, Gapdh (glyceraldehyde-3-phosphate dehydrogenase) [NCBI Gene 14433] {aka Gapd}, MMP2 (matrix metallopeptidase 2) [NCBI Gene 4313] {aka CLG4, CLG4A, MMP-2, MMP-II, MONA, TBE-1}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53}, GJA1 (gap junction protein alpha 1) [NCBI Gene 2697] {aka AVSD3, CMDR, CX43, EKVP, EKVP3, GJAL}, CDKN2A (cyclin dependent kinase inhibitor 2A) [NCBI Gene 1029] {aka ARF, CAI2, CDK4I, CDKN2, CMM2, INK4}, Cdkn1a (cyclin dependent kinase inhibitor 1A) [NCBI Gene 12575] {aka CAP20, CDKI, CIP1, Cdkn1, P21, SDI1}, H3P16 (H3 histone pseudogene 16) [NCBI Gene 644914] {aka H3.6, H3F3AP6, p21}, MAPK14 (mitogen-activated protein kinase 14) [NCBI Gene 1432] {aka CSBP, CSBP1, CSBP2, CSPB1, EXIP, Mxi2} - **Diseases:** fibrosis (MESH:D005355), inflammation (MESH:D007249), VSM (MESH:D014811), diabetic foot ulcers (MESH:D017719), injuries (MESH:D014947), skin complications (MESH:D012871), cancer (MESH:D009369), diabetic (MESH:D003920), infection (MESH:D007239), atrophy (MESH:D001284), ulcers (MESH:D014456), Cytotoxicity (MESH:D064420), vascular damage (MESH:D057772), breast cancer (MESH:D001943), organ dysfunction (MESH:D009102), venous leg ulcers (MESH:D014647), atopic dermatitis (MESH:D003876), radiation injury to the skin (MESH:D011832) - **Chemicals:** SDC (MESH:D003840), glycolic acid (MESH:C031149), potassium acetate (MESH:D019347), bile acids (MESH:D001647), WST-8 (MESH:C476329), NaCl (MESH:D012965), SM (MESH:D013109), methanol (MESH:D000432), olive oil (MESH:D000069463), paraffin (MESH:D010232), N-Lauroylsarcosine (MESH:C025231), Buffered Saline (-), formazan (MESH:D005562), phalloidin (MESH:D010590), BIRB796 (MESH:C452139), glycerol (MESH:D005990), penicillin (MESH:D010406), Nile Red (MESH:C044808), D-alpha-tocopherol polyethylene glycol 1000 succinate (MESH:C014225), bis-acrylamide (MESH:C021221), quercetin (MESH:D011794), Vit E (MESH:D014810), bromophenol blue (MESH:D001978), EDTA (MESH:D004492), amphotericin B (MESH:D000666), dasatinib (MESH:D000069439), phenylmethylsulfonyl fluoride (MESH:D010664), Nonidet P-40 (MESH:C010615), X-Gal (MESH:C044888), streptomycin (MESH:D013307), Triton X-100 (MESH:D017830), TFA (MESH:D014269), acetonitrile (MESH:C032159), CO2 (MESH:D002245), water (MESH:D014867), polyphenol (MESH:D059808), CCK-8 (MESH:D012844), tetrazolium salt (MESH:D013778), STC (MESH:D013656), Ponceau S red (MESH:C032756), paraformaldehyde (MESH:C003043), Lipid (MESH:D008055), chloroform (MESH:D002725), SDS (MESH:D012967), acetic acid (MESH:D019342), PVDF (MESH:C024865), OLP (MESH:C002769), sphingolipids (MESH:D013107), Tween 20 (MESH:D011136), PBS (MESH:D007854), 5(6)-carboxyfluorescein (MESH:C024098), glutaraldehyde (MESH:D005976), methacrylate (MESH:D008689), navitoclax (MESH:C528561), ceramides (MESH:D002518), glycine (MESH:D005998), DAPI (MESH:C007293), DMSO (MESH:D004121), acrylamide (MESH:D020106), ethanol (MESH:D000431) - **Species:** Olea europaea (common olive, species) [taxon 4146], Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606], Canis lupus familiaris (dog, subspecies) [taxon 9615], Mycoplasma (genus) [taxon 2093], Oryctolagus cuniculus (domestic rabbit, species) [taxon 9986] - **Cell lines:** fibroblasts — Mus musculus (Mouse), Spontaneously immortalized cell line (CVCL_0594) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12918234/full.md ## Figures 8 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12918234/full.md ## References 114 references — full list in the complete paper: https://tomesphere.com/paper/PMC12918234/full.md --- Source: https://tomesphere.com/paper/PMC12918234