Hydrogels evolved as an outstanding carrier material for local and controlled drug delivery that tend to overcome the shortcomings of old conventional dosage forms for small drugs (NSAIDS) and large peptides and proteins. The aqueous swellable and crosslinked polymeric network structure of hydrogels is composed of various natural, synthetic and semisynthetic biodegradable polymers. Hydrogels have remarkable properties of functionality, reversibility, sterilizability, and biocompatibility. All these dynamic properties of hydrogels have increased the interest in their use as a carrier for peptides and proteins to be released slowly in a sustained manner. Peptide and proteins are remarkable therapeutic agents in today’s world that allow the treatment of severe, chronic and life-threatening diseases, such as diabetes, rheumatoid arthritis, hepatitis. Despite few limitations, hydrogels provide fine tuning of proteins and peptides delivery with enormous impact in clinical medicine. Novels drug delivery systems composed of smart peptides and molecules have the ability to drive self-assembly and form hydrogels at physiological pH. These hydrogels are significantly important for biological and medical fields. The primary objective of this article is to review current issues concerned with the therapeutic peptides and proteins and impact of remarkable properties of hydrogels on these therapeutic agents. Different routes for pharmaceutical peptides and proteins and superiority over other drugs candidates are presented. Recent advances based on various approaches like self-assembly of peptides and small molecules to form novel hydrogels are also discussed. The article will also review the literature concerning the classification of hydrogels on a different basis, polymers used, “release mechanisms” their physical and chemical characteristics and diverse applications.

The effective clinical translation of messenger RNA (mRNA), small interfering RNA (siRNA), and microRNA (miRNA) for therapeutic purposes hinges on the development of efficient delivery systems. Key challenges include their susceptibility to degradation, limited cellular uptake, and inefficient intracellular release. Polymeric drug conjugates (PDCs) offer a promising solution, combining the benefits of polymeric carriers and therapeutic agents for targeted delivery and treatment. This comprehensive review explores the clinical translation of nucleic acid therapeutics, focusing on polymeric drug conjugates. It investigates how these conjugates address delivery obstacles, enhance systemic circulation, reduce immunogenicity, and provide controlled release, improving safety profiles. The review delves into the conjugation strategies, preparation methods, and various classes of PDCs, as well as strategic design, highlighting their role in nucleic acid delivery. Applications of PDCs in treating diseases such as cancer, immune disorders, and fibrosis are also discussed. Despite significant advancements, challenges in clinical adoption persist. The review concludes with insights into future directions for this transformative technology, underscoring the potential of PDCs to advance nucleic acid-based therapies and combat infectious diseases significantly.

Background: Liver fibrosis is a chronic liver disease associated with an excessive accumulation of extracellualr matrix (ECM) proteins which ultimately lead to cirrohosis and hepatocellular carcinoma. Purpose: Liver fibrosis therapies that use combination approaches with the ability to affect multiple disease pathways have proven higher efficacies. This study aimed at optimizing and characterizing the co-encapsulation of pirfenidone (PF) and AMD3100 (AMD) into CXCR4-targeted combination liposomes (CTC liposome) for CXCR4 targeting, and the inhibition of major molecular culprits ie α-SMA, CXCR4, TGFβ, and P-p38 involved in liver fibrosis in-vitro. Methods: The CTC liposomes were prepared using the thin-film hydration method. The concentration of encapsulated AMD and PF was measured by HPLC and UV spectrophotometry, respectively. Tramsmission electron microscopy (TEM) was used to determine the liposomal morphology. The CXCR4 targeting ability was determined by CXCR4 redistribution assay. Confocal microscopy and flowcytometry were used to determine the CXCR4 mediated cell uptake. The apoptosis inducing and protein downreguating ability of CTC liposomes were determined by apoptosis assay and western blot analysis, respectively. In-vivo biodistribution and Hoechst staining were used to confirm the feasibility of CTC liposome for the in-vivo applications and drug targeted accumulation, respectively. Results: The TEM studies revealed that CTC liposomes were spherical in shape. The cumulative release of AMD and PF from CTC liposome was 67% and 84%, respectively, at 48 h. Compared to the free drug counterparts, encapsulated drugs displayed higher cell viability. The CXCR4 redistribution assay confirmed the CXCR4 targeting and antagonistic ability of CTC liposomes. The CTC liposomes were internalized more effectively via caveolae-mediated endocytic pathways. CTC liposomes displayed aggressive apoptosis (87.3%) in TGFβ-induced activated HSC-T6 cells suggesting a propensity to fibrosis regression. Also, CTC liposomes significantly reduced α-SMA (65%), CXCR4 (77%), TGFβ (89%), and P-p38 (66%) expressions, better than free drugs. CTC@IR780 liposomes (CTC liposomes incorporating IR780 dye) were more accumulated in fibrotic livers compared to free IR780, as judged by in-vivo imaging, biodistribution analysis, and Hoechst staining. These findings suggest that this simple and stable CTC liposomal system holds a great promise for the treatment and prevention of liver fibrosis.

We propose a chemokine receptor 4 (CXCR4)-targeted combination (CTC) liposomal therapy to treat carbon tetrachloride (CCl ₄ )-induced liver fibrosis. CTC lipo reverses the liver fibrosis to normalization.

Background: Liver fibrosis is a chronic liver disease with excessive production of extracellular matrix proteins, leading to cirrhosis, hepatocellular carcinoma, and death. Purpose: This study aimed at the development of a novel derivative of polyethyleneimine (PEI) that can effectively deliver transforming growth factor β (TGFβ) siRNA and inhibit chemokine receptor 4 (CXCR4) for TGFβ silencing and CXCR4 Inhibition, respectively, to treat CCl₄-induced liver fibrosis in a mouse model. Methods: Cyclam-modified PEI (PEI-Cyclam) was synthesized by incorporating cyclam moiety into PEI by nucleophilic substitution reaction. Gel electrophoresis confirmed the PEI-Cyclam polyplex formation and stability against RNAase and serum degradation. Transmission electron microscopy and zeta sizer were employed for the morphology, particle size, and zeta potential, respectively. The gene silencing and CXCR4 targeting abilities of PEI-Cyclam polyplex were evaluated by luciferase and CXCR4 redistribution assays, respectively. The histological and immunohistochemical staining determined the anti-fibrotic activity of PEI-Cyclam polyplex. The TGFβ silencing of PEI-Cyclam polyplex was authenticated by Western blotting. Results: The ¹H NMR of PEI-Cyclam exhibited successful incorporation of cyclam content onto PEI. The PEI-Cyclam polyplex displayed spherical morphology, positive surface charge, and stability against RNAse and serum degradation. Cyclam modification decreased the cytotoxicity and demonstrated CXCR4 antagonistic and luciferase gene silencing efficiency. PEI-Cyclam/siTGFβ polyplexes decreased inflammation, collagen deposition, apoptosis, and cell proliferation, thus ameliorating liver fibrosis. Also, PEI-Cyclam/siTGFβ polyplex significantly downregulated α-smooth muscle actin, TGFβ, and collagen type III. Conclusion: Our findings validate the feasibility of using PEI-Cyclam as a siRNA delivery vector for simultaneous TGFβ siRNA delivery and CXCR4 inhibition for the combined anti-fibrotic effects in a setting of CCl₄-induced liver fibrosis.