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Targeted and efficient gene delivery systems hold tremendous potential for the improvement of cancer therapy by enabling appropriate modification of biological processes. Herein, we report the design and synthesis of a novel cationic di-block copolypeptide, incorporating homoarginine (HAG) and shikimoyl (LSA) functionalities (HDA-b-PHAGm-b-PLSAn), tailored for enhanced gene transfection specifically in cancer cells. The di-block copolypeptide was synthesized via sequential N-carboxyanhydride (NCA) ring-opening polymerization (ROP) techniques and its physicochemical properties were characterized, including molecular weight, dispersity, secondary conformation, size, morphology, and surface charge. In contrast to the cationic poly- L -homoarginine, we observed a significantly reduced cytotoxic effect of this di-block copolypeptide due to the inclusion of the shikimoyl glyco-polypeptide block, which also added selectivity in internalizing particular cells. This di-block copolypeptide was internalized via mannose-receptor-mediated endocytosis, which was investigated by competitive receptor blocking with mannan. We evaluated the transfection efficiency of the copolypeptide in HEK 293T (noncancerous cells), MDA-MB-231 (breast cancer cells), and RAW 264.7 (dendritic cells) and compared it with commonly employed transfection agents (Lipofectamine). Our findings demonstrate that the homoarginine and shikimoyl-functionalized cationic di-block copolypeptide exhibits potent gene transfection capabilities with minimal cytotoxic effects, particularly in cancer cells, while it is ineffective for normal cells, indicative of its potential as a promising platform for cancer cell-specific gene delivery systems. To evaluate this, we delivered an artificially designed miRNA-plasmid against Hsp90 (amiR-Hsp90) which upon successful transfection depleted the Hsp90 (a chaperone protein responsible for tumour growth) level specifically in cancerous cells and enforced apoptosis. This innovative approach offers a new avenue for the development of targeted therapeutics with an improved efficacy and safety profile in cancer treatment. [ABSTRACT FROM AUTHOR]

Aim: To assess the chemo-immunomodulatory effects of doxorubicin-loaded cerium oxide nanoparticles coated with oleyl amine-linked cyclic RGDfK peptide (CeNP+Dox+RGD) to target both gliomas and its tumor microenvironment (TME) via integrin receptors. Materials & methods: CeNP+Dox+RGD nanoparticles are synthesized by the sequential addition of cerium III chloride heptahydrate, beta-cyclodextrin, oleic acid, and F127 micelle (CeNP). Doxorubicin was then loaded into CeNPs and coated with oleyl amine-linked cyclic RGDfK peptide to form stable CeNP+Dox+RGD nanoparticles. Results: CeNP+Dox+RGD nanoparticles crossed blood–brain barrier (BBB) effectively and demonstrated threefold enhanced survivability in glioma-bearing mice. The IHC profiling of glial tumor cross-sections showed increased CD80 expression (M1 TAMs) and decreased arginase-1 expression (M2 TAMs). Conclusion: CeNP+Dox+RGD can be an immunotherapeutic treatment option to combat glioblastoma. Article highlights The complexity of the brain's blood–brain barrier and the cross-talk between gliomas with their surrounding tumor microenvironment (TME) often impact the effectiveness of conventional regimens for glioblastoma (GBM) treatment. Doxorubicin (Dox) loaded cerium oxide nanoparticles (CeNPs) coated with oleyl amine-linked cyclic RGDfK peptide (CeNP+Dox+RGD) were synthesized to target both the gliomas and its TME. The first study was to evaluate both the anticancer properties and immunomodulatory effects of CeNP+Dox+RGD nanoparticles via integrin receptors in the orthotopic glioma model in mice. The functionalization of nanoparticles with RGD peptide facilitated their translocation across the blood–brain barrier successfully. A three-fold increase in the survivability of mice with CeNP+Dox+RGD treatment was observed compared with control and other treated groups in the orthotopic mice glioma models. Increased expression of CD80 marker associated with anticancer M1 phenotype of tumor-associated macrophages (TAMs) with CeNP+Dox+RGD treatment. Decreased expression of Arginase-1 marker associated with recruitment of immunosuppressive M2 phenotype TAMs in orthotopic glioma model in mice. CeNP+Dox+RGD treatment can enhance the current immunotherapeutic strategies to combat gliomas via integrin receptors. [ABSTRACT FROM AUTHOR]