Targeting neuroblastoma by small-molecule inhibitors of human ALYREF protein: mechanistic insights using molecular dynamics simulations.

Neuroblastoma is a tumour of the sympathetic nervous system mainly prevalent in children. Many strategies have been employed to target several drug-targetable proteins for the clinical management of neuroblastoma. However, the heterogeneous nature of neuroblastoma presents serious challenges in drug development for its treatment. Albeit numerous medications have been developed to target various signalling pathways in neuroblastoma, the redundant nature of the tumour pathways makes its suppression unsuccessful. Recently, the quest for neuroblastoma therapy resulted in the identification of human ALYREF, a nuclear protein that plays an essential role in tumour growth and progression. Therefore, this study used the structure-based drug discovery method to identify the putative inhibitors targeting ALYREF for the Neuroblastoma treatment. Herein, a library of 119 blood-brain barrier crossing small molecules from the ChEMBL database was downloaded and docked against the predicted binding pocket of the human ALYREF protein. Based on docking scores, the top four compounds were considered for intermolecular interactions and molecular dynamics simulation analysis, which revealed CHEMBL3752986 and CHEMBL3753744 with substantial affinity and stability with the ALYREF. These results were further supported by binding free energies and essential dynamics analysis of the respective complexes. Hence, this study advocates the sorted compounds targeting ALYREF for further in vitro and in vivo assessment to develop a drug against neuroblastoma.Communicated by Ramaswamy H. Sarma.

In Silico Study of a Small Bioactive Molecule Targeting Topoisomerase II and P53-MDM2 Complex in Triple-Negative Breast Cancer.

Treatment of triple-negative breast cancer (TNBC) is very challenging as only few therapeutic options are available, including chemotherapy. Thus, a constant search for new and effective approaches of therapy that could potentially fight against TNBC and mitigate side effects is "turn-on". Recently, multitarget therapy has come up with huge possibilities, and it may possibly be useful to overcome several concurrent challenges in cancer therapy. Herein, we proposed the inhibition of both Topoisomerase II enzyme and p53-MDM2 (p53 cavity in MDM2) protein complex by the same bioactive molecules for multitarget therapy. RNA-seq analysis was performed to get a network of essential proteins involved in the apoptosis pathway by considering the triple-negative breast cancer cell line (MDA-MB-231). All of the untreated duplicate sample data were retrieved from NCBI (GSC149768). Further, via in silico screening, potent bioactive molecules were screened out to target both Topo II and the p53-MDM2 complex. The results of ligand-based screening involving docking, MMGBSA, ADME/T, MD simulation, and PCA suggested that resveratrol, a plant bioactive molecule, showed more potential binding in the same cavity of target proteins compared with doxorubicin for Topo IIα (5GWK) and etoposide for the second protein target (p53-MDM2 complex; 4OQ3) as the control drug. This is also evident from the in vitro validation in case of triple-negative breast cancer cell lines (MDA-MB-231) and Western blotting analysis. Thus, it paves the scope of multitargeting against triple-negative breast cancer.

Identification of naturally occurring compounds as alternatives to radiation therapy for treatment of small cell lung cancer.

Radiation resistance is one of the major problems in the treatment of small cell lung cancer (SCLC). Most of these patients are given radiation as first-line treatment and it was observed that the initial response in these patients is very good. However, they show relapse in a few months which is also associated with resistance to treatment. Thus, targeting the mechanism by which these cells develop resistance could be an important strategy to improve the survival chances of these patients. From the RNA-Seq data analysis, it was identified that CHEK1 gene was overexpressed. Chk1 protein which is encoded by the CHEK1 gene is an important protein that is involved in radiation resistance in SCLC. It is known to favour the cells to deal with replicative stress. CHEK1 is the major cause for developing radiation resistance in SCLC. Thus, natural compounds that could also serve as potential inhibitors for Chk1 were explored. Accordingly; the compounds were screened based on ADME, docking and MM-GBSA scores. MD simulations were performed for the selected protein-ligand complexes and the results were compared to the co-crystallised ligand, 3-(indol-2-yl)indazole. The results showed that compound INC000033832986 could be a natural alternative to the commercial ligand for the prevention of SCLC.Communicated by Ramaswamy H. Sarma.

Strategies in design of self-propelling hybrid micro/nanobots for bioengineering applications.

Micro/nanobots are integrated devices developed from engineered nanomaterials that have evolved significantly over the past decades. They can potentially be pre-programmed to operate robustly at numerous hard-to-reach organ/tissues/cellular sites for multiple bioengineering applications such as early disease diagnosis, precision surgeries, targeted drug delivery, cancer therapeutics, bio-imaging, biomolecules isolation, detoxification, bio-sensing, and clearing up clogged arteries with high soaring effectiveness and minimal exhaustion of power. Several techniques have been introduced in recent years to develop programmable, biocompatible, and energy-efficient micro/nanobots. Therefore, the primary focus of most of these techniques is to develop hybrid micro/nanobots that are an optimized combination of purely synthetic or biodegradable bots suitable for the execution of user-defined tasks more precisely and efficiently. Recent progress has been illustrated here as an overview of a few of the achievable construction principles to be used to make biomedical micro/nanobots and explores the pivotal ventures of nanotechnology-moderated development of catalytic autonomous bots. Furthermore, it is also foregrounding their advancement offering an insight into the recent trends and subsequent prospects, opportunities, and challenges involved in the accomplishments of the effective multifarious bioengineering applications.

Exploration of Microbially Derived Natural Compounds against Monkeypox Virus as Viral Core Cysteine Proteinase Inhibitors.

Monkeypox virus (MPXV) is a member of the Orthopoxvirus genus and the Poxviridae family, which instigated a rising epidemic called monkeypox disease. Proteinases are majorly engaged in viral propagation by catalyzing the cleavage of precursor polyproteins. Therefore, proteinase is essential for monkeypox and a critical drug target. In this study, high-throughput virtual screening (HTVS) and molecular dynamics simulation were applied to detect the potential natural compounds against the proteinase of the monkeypox virus. Here, 32,552 natural products were screened, and the top five compounds were selected after implementing the HTVS and molecular docking protocols in series. Gallicynoic Acid F showed the minimum binding score of -10.56 kcal/mole in the extra precision scoring method, which reflected the highest binding with the protein. The top five compounds showed binding scores ≤-8.98 kcal/mole. These compound complexes were tested under 100 ns molecular dynamics simulation, and Vaccinol M showed the most stable and consistent RMSD trend in the range of 2 Å to 3 Å. Later, MM/GBSA binding free energy and principal component analysis were performed on the top five compounds to validate the stability of selected compound complexes. Moreover, the ligands Gallicynoic Acid F and H2-Erythro-Neopterin showed the lowest binding free energies of -61.42 kcal/mol and -61.09 kcal/mol, respectively. Compared to the native ligand TTP-6171 (ΔGBind = -53.86 kcal/mol), these two compounds showed preferable binding free energy, suggesting inhibitory application against MPXV proteinase. This study proposed natural molecules as a therapeutic solution to control monkeypox disease.

Recent development of multi-targeted inhibitors of human topoisomerase II enzyme as potent cancer therapeutics.

Multi-target therapies have been considered one of the viable options to overcome the challenges to eradicate intrinsic and acquired drug-resistant cancer cells. While to increase the efficacy of therapeutics, the use of a single drug against multiple structurally similar sites, which noncommittedly modulate several vital cellular pathways proposed as a potential alternative to a 'single drug single target'. Besides, it reduces the usage of a number of drugs and their side effects. Topoisomerase II enzyme plays a very significant role in DNA replication and thus served as an important target for numerous anti-cancer agents. However, in spite of promising clinical results, in several cases, it was found that cancer cells have developed resistance against the anti-cancer agents targeting this enzyme. Therefore, multi-target therapies have been proposed as an alternative to overcome different drug resistance mechanisms while topoisomerases II are a primary target site. In this review, we have tried to discuss the characteristics of the binding cavity available for interactions of drugs, and potent inhibitors concurrently modulate the functions of topoisomerases II as well as other structurally related target sites. Additionally, the mechanism of drug resistance by considering molecular and cellular insights by including various types of cancers.

Docking and molecular dynamics simulation for therapeutic repurposing in small cell lung cancer (SCLC) patients infected with COVID-19.

Cancer care has become a challenge with the current COVID-19 pandemic scenario. Specially, cancers like small cell lung cancers (SCLC) are difficult to treat even in the normal situation due to their rapid growth and early metastasis. For such patients, treatment can't be compromised and care must be taken to ensure their minimum exposure to the ongoing spread of COVID-19 infection. For this reason, in-house treatments are being suggested for these patients. Another issue is that symptoms of SCLC match well with that of COVID-19 infection. Hence, the detection of COVID-19 may also get delayed leading to unnecessary complications. Thus, we have tried to investigate if the therapeutics that is currently used in lung cancer treatment can also act against SARS-CoV-2. If it is so, the same treatment protocols can be continued even if the SCLC patient had contracted COVID-19 without compromising the cancer care. For this, RNA dependent RNA polymerase (RdRP) from SARS-CoV-2 has been selected as drug target. Both docking and molecular dynamicssimulation analysis have indicated that Paclitaxel and Dacomitinib may be explored as multi-target drugs for both SCLC and COVID-19.Communicated by Ramaswamy H. Sarma.

Nanoengineering of biohybrid micro/nanobots for programmed biomedical applications.

Biohybrid micro/nanobots have emerged as an innovative resource to be employed in the biomedical field due to their biocompatible and biodegradable properties. These are tiny nanomaterial-based integrated structures engineered in a way that they can move autonomously and perform the programmed tasks efficiently even at hard-to-reach organ/tissues/cellular sites. The biohybrid micro/nanobots can either be cell/bacterial/enzyme-based or may mimic the properties of an active molecule. It holds the potential to change the landscape in various areas of biomedical including early diagnosis of disease, therapeutics, imaging, or precision surgery. The propulsion mechanism of the biohybrid micro/nanobots can be both fuel-based and fuel-free, but the most effective and easiest way to propel these micro/nanobots is via enzymes. Micro/nanobots possess the feature to adsorb/functionalize chemicals or drugs at their surfaces thus offering the scope of delivering drugs at the targeted locations. They also have shown immense potential in intracellular sensing of biomolecules and molecular events. Moreover, with recent progress in the material development and processing is required for enhanced activity and robustness the fabrication is done via various advanced techniques to avoid self-degradation and cause cellular toxicity during autonomous movement in biological medium. In this review, various approaches of design, architecture, and performance of such micro/nanobots have been illustrated along with their potential applications in controlled cargo release, therapeutics, intracellular sensing, and bioimaging. Furthermore, it is also foregrounding their advancement offering an insight into their future scopes, opportunities, and challenges involved in advanced biomedical applications.

Computational Investigations on the Natural Small Molecule as an Inhibitor of Programmed Death Ligand 1 for Cancer Immunotherapy.

Several therapeutic monoclonal antibodies approved by the FDA are available against the PD-1/PD-L1 (programmed death 1/programmed death ligand 1) immune checkpoint axis, which has been an unprecedented success in cancer treatment. However, existing therapeutics against PD-L1, including small molecule inhibitors, have certain drawbacks such as high cost and drug resistance that challenge the currently available anti-PD-L1 therapy. Therefore, this study presents the screening of 32,552 compounds from the Natural Product Atlas database against PD-L1, including three steps of structure-based virtual screening followed by binding free energy to refine the ideal conformation of potent PD-L1 inhibitors. Subsequently, five natural compounds, i.e., Neoenactin B1, Actinofuranone I, Cosmosporin, Ganocapenoid A, and 3-[3-hydroxy-4-(3-methylbut-2-enyl)phenyl]-5-(4-hydroxybenzyl)-4-methyldihydrofuran-2(3H)-one, were collected based on the ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling and binding free energy (>−60 kcal/mol) for further computational investigation in comparison to co-crystallized ligand, i.e., JQT inhibitor. Based on interaction mapping, explicit 100 ns molecular dynamics simulation, and end-point binding free energy calculations, the selected natural compounds were marked for substantial stability with PD-L1 via intermolecular interactions (hydrogen and hydrophobic) with essential residues in comparison to the JQT inhibitor. Collectively, the calculated results advocate the selected natural compounds as the putative potent inhibitors of PD-L1 and, therefore, can be considered for further development of PD-L1 immune checkpoint inhibitors in cancer immunotherapy.

In silico study indicates antimalarials as direct inhibitors of SARS-CoV-2-RNA dependent RNA polymerase.

Coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused a global pandemic. RNA-dependent RNA polymerase (RdRp) is the key component of the replication or transcription machinery of coronavirus. Therefore SARS-CoV-2-RdRp has been chosen as an important target for the development of antiviral drug(s). During the early pandemic of the COVID-19, chloroquine and hydroxychloroquine were suggested by the researchers for the prevention or treatment of SARS-CoV-2. In our study, the antimalarial compounds have been screened and docked against SARS-CoV-2-RdRp (PDB ID: 7BTF), and it was observed that the antimalarials chloroquine, hydroxychloroquine, and amodiaquine exhibit good affinity. Since the crystal structure of SARS-CoV-2-RdRp with its substrate is not available, poliovirus-RdRp crystal structure co-crystallized with its substrate ATP (PDB ID: 2ILY) was used as a reference structure. The superimposition of SARS-CoV-2-RdRp and poliovirus-RdRp structures showed that the active sites of both of the RdRps superimposed very well. The amino acid residues involved in the binding of ATP in the case of poliovirus-RdRp and residues involved in binding with the antimalarial compounds with SARS-CoV-2-RdRp were compared. In both cases, the conserved residues were found to be involved in establishing the interactions. The MMGBSA and molecular dynamic simulation studies were performed to strengthen our docking results. Further residues involved in binding of antimalarials with SARS-CoV-2-RdRp were compared with the residues involved in the SARS-CoV-2-RdRp complexed with remdesivir [PDB ID: 7BV2]. It was observed that co-crystallized remdesivir and docked antimalarials bind in the same pocket of SARS-CoV-2 -RdRp.Communicated by Ramaswamy H. Sarma.

Determination of tyrosinase-cyanidin-3-O-glucoside and (-/+)-catechin binding modes reveal mechanistic differences in tyrosinase inhibition.

Tyrosinase, exquisitely catalyzes the phenolic compounds into brown or black pigment, inhibition is used as a treatment for dermatological or neurodegenerative disorders. Natural products, such as cyanidin-3-O-glucoside and (-/+)-catechin, are considered safe and non-toxic food additives in tyrosinase inhibition but their ambiguous inhibitory mechanism against tyrosinase is still elusive. Thus, we presented the mechanistic insights into tyrosinase with cyanidin-3-O-glucoside and (-/+)-catechin using computational simulations and in vitro assessment. Initial molecular docking results predicted ideal docked poses (- 9.346 to - 5.795 kcal/mol) for tyrosinase with selected flavonoids. Furthermore, 100 ns molecular dynamics simulations and post-simulation analysis of docked poses established their stability and oxidation of flavonoids as substrate by tyrosinase. Particularly, metal chelation via catechol group linked with the free 3-OH group on the unconjugated dihydropyran heterocycle chain was elucidated to contribute to tyrosinase inhibition by (-/+)-catechin against cyanidin-3-O-glucoside. Also, predicted binding free energy using molecular mechanics/generalized Born surface area for each docked pose was consistent with in vitro enzyme inhibition for both mushroom and murine tyrosinases. Conclusively, (-/+)-catechin was observed for substantial tyrosinase inhibition and advocated for further investigation for drug development against tyrosinase-associated diseases.

Repurposing of gastric cancer drugs against COVID-19.

Corona Virus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has become a global pandemic. Additionally, the SARS-CoV-2 infection in the patients of Gastric Cancer (GC; the third leading cause of death in the world) pose a great challenge for the health management of the patients. Since there have been uncertainties to develop a new drug against COVID-19, there is an urgent need for repurposing drugs that can target key proteins of both SARS-CoV-2 and GC. The SARS-CoV-2-RdRp protein contains the NiRAN domain, which is known to have kinase-like folds. A docking study of the FDA approved drugs against GC was performed using AutoDock 4.2 and Glide Schrodinger suite 2019 against SARS-CoV-2-RdRp protein. MMGBSA and MD simulation studies were performed to investigate the binding and stability of the inhibitors with the target protein. In this study, we have found 12 kinase inhibitors with high binding energies namely Baricitinib, Brepocitinib, Decernotinib, Fasudil, Filgotinib, GSK2606414, Peficitinib, Ruxolitinib, Tofacitinib, Upadacitinib, Pamapimod and Ibrutinib. These FDA approved drugs against GC can play a key role in the treatment of COVID-19 patients along with GC as comorbidity. We also hypothesize that JAK, ITK, Rho-associated kinases, FGFR2, FYN, PERK, TYK2, p38-MAPK and SYK kinases can be considered as key therapeutic targets in COVID-19 treatment. Taken altogether, we have proposed the SARS-CoV-2-RdRp as a potential therapeutic target through in-silico studies. However, further in-vitro and in-vivo studies are required for the validation of the proposed targets and drugs for the treatment of COVID-19 patients already suffering from GC.

Drug repurposing for ligand-induced rearrangement of Sirt2 active site-based inhibitors via molecular modeling and quantum mechanics calculations.

Sirtuin 2 (Sirt2) nicotinamide adenine dinucleotide-dependent deacetylase enzyme has been reported to alter diverse biological functions in the cells and onset of diseases, including cancer, aging, and neurodegenerative diseases, which implicate the regulation of Sirt2 function as a potential drug target. Available Sirt2 inhibitors or modulators exhibit insufficient specificity and potency, and even partially contradictory Sirt2 effects were described for the available inhibitors. Herein, we applied computational screening and evaluation of FDA-approved drugs for highly selective modulation of Sirt2 activity via a unique inhibitory mechanism as reported earlier for SirReal2 inhibitor. Application of stringent molecular docking results in the identification of 48 FDA-approved drugs as selective putative inhibitors of Sirt2, but only top 10 drugs with docking scores > - 11 kcal/mol were considered in reference to SirReal2 inhibitor for computational analysis. The molecular dynamics simulations and post-simulation analysis of Sirt2-drug complexes revealed substantial stability for Fluphenazine and Nintedanib with Sirt2. Additionally, developed 3D-QSAR-models also support the inhibitory potential of drugs, which exclusively revealed highest activities for Nintedanib (pIC50 ≥ 5.90 µM). Conclusively, screened FDA-approved drugs were advocated as promising agents for Sirt2 inhibition and required in vitro investigation for Sirt2 targeted drug development.

Modulating catalytic activity of human topoisomerase II α enzyme by fluorescent gold nanoclusters.

Precise monitoring of the enzyme activity by a suitable modulator is one of the very fundamental aspects of drug designing that provides the opportunity to overcome the challenges of several diseases. Herein, inhibition of human Topoisomerase IIα enzyme which serves as a potential target site for several anti-cancer drugs is demonstrated by using ultra-small size gold nanoclusters (Au NCs) with the dimension comparable with size of the active site of the enzyme. Molecular dynamics simulation results demonstrate that the Au NCs strongly interact with the human Topo IIα enzyme at its active site or allosteric site depending on forms of enzyme. Additionally, binding energy and interaction profile provides the molecular basis of understanding of interactions of ultra-small size Au NCs and human Topo IIα enzyme. Enthalpy change (ΔH) and binding constant (K) are measured based on a sequential binding model of the Au NCs with the enzyme as demonstrated by the ITC study. Moreover, the in-vitro inhibition study of the catalytic activity of the enzyme and gel electrophoresis indicates that the ultra-small size Au NCs may be used as a potent inhibitor of human Topo IIα enzyme.

Pathways in small cell lung cancer and its therapeutic perspectives.

Small cell lung cancer (SCLC) is known for its rapid growth with high metastatic spread. Its treatment remains a major challenge for oncologists due to the high mutation rate and other clinical disadvantages. The survival rate of these patients is very poor but there is no significant progress over the last few decades in the treatment protocols. Hence there is an urgency to design new clinical trials with novel drug combinations that can specifically and effectively target key pathways for proper treatment of SCLC. There have been several indications that developmental signalling pathways are involved in tumor growth, progression, metastasis and invasion of SCLC. Thus, it is anticipated that deciphering the signalling cascades of these embryonic signalling pathways may reveal novel therapeutic breakthroughs in SCLC. In this context, we have tried to assemble all the relevant information to give an updated overview of the various signalling pathways involved in the development of SCLC.

Single Platform for Gene and Protein Expression Analyses Using Luminescent Gold Nanoclusters.

A single platform for gene and protein expression studies is proposed to pursue rapid diagnostics. A common method to synthesize gold (Au) nanoclusters on both DNA and protein template was developed using a benchtop device. The method of synthesis is rapid and versatile and can be applied to different classes of DNA/protein. Employing luminescent Au nanoclusters as the signal-generating agents, the device enables carrying out reverse transcriptase polymerase chain reaction and array-based analyses of multiple genes/proteins simultaneously using switchable holders and custom-designed software. The device and methods were applied to evaluate gene profiling related to apoptosis in HeLa cancer cells and further to analyze the protein expressions of glutathione-S-transferase (GST) and GST-tagged human granulocyte macrophage colony-stimulating factor (GST-hGMCSF) recombinant proteins purified from bacterial strains of BL21(DE3) Escherichia coli (E. coli). The device with user-friendly methods for diagnosis using the luminescence of Au nanoclusters offers potential use in disease diagnostics with a vision to extend health care facilities especially to remote geographical locations.

Receptor-Mediated Enhanced Cellular Delivery of Nanoparticles Using Recombinant Receptor-Binding Domain of Diphtheria Toxin.

Antibodies and peptides are often used to home nanoparticles (NPs) to specific cells. Here in this work, we have used recombinant receptor-binding domain of diphtheria toxin (RDT) as a homing molecule for NPs. Diphtheria toxin binds to heparin binding EGF-like growth factor (HB-EGF) through its receptor-binding domain. HB-EGF is often overexpressed as cell surface molecule in various types of cancer. We have prepared monodispersed, spherical PLGA NPs and coated these NPs with RDT. These NPs are characterized by FESEM and FT-IR spectroscopy. Using flow cytometry and fluorescence spectroscopy, we show that coating with RDT increases cellular uptake of PLGA NPs. We further show that RDT-coated nanoparticles are internalized through clathrin-dependent receptor-mediated endocytosis that can be reduced by specific inhibitor. These RDT-coated nanoparticles (RDT-NP) were further used for preferential delivery of Irinotecan, a chemotherapeutic agent, to cells overexpressing HB-EGF. We show that receptor-mediated enhanced uptake of RDT-NPs increases the potency of irinotecan in these cells.

Bimetallic silver nanoparticle-gold nanocluster embedded composite nanoparticles for cancer theranostics.

A bimetallic silver nanoparticle based gold nanocluster module has been developed for theranostic cellular application by a rapid and simple galvanic exchange method. The use of chitosan as a template has helped to convert the bimetallic system into composite nanoparticles, which can be easily delivered into cancer cells. The synthesized composite nanoparticles offer the advantage of combinatorial properties of the metals present in two different nanoscale levels enabling both killing and bioimaging of cancer cells. Detailed molecular events of cell death were illustrated for this combined module to decipher apoptotic mediated cell death.

Silver Nanocluster Embedded Composite Nanoparticles for Targeted Prodrug Delivery in Cancer Theranostics.

Cancer therapy with theranostic nanoparticles having the dual properties of concurrent delivery of therapeutics and its tracking offers a huge prospect to overcome the limitations of conventional therapy. Delivery of the nontoxic prodrug, which converts into the toxic drug due to cellular stimuli, offers a great deal of scope in cancer therapy. The paracetamol dimer (PD) generally considered as nontoxic is encapsulated with fluorescent silver nanocluster (Ag NC) embedded composite nanoparticles where it acts as a prodrug. This is possibly converted to a toxic metabolite due to elevated reactive oxygen species (ROS), leading to apoptosis mediated cell death. Conjugation of folic acid with these composite NPs offers the credibility of distinguishing between two different cancer cell lines such as HeLa, which overexpresses folic acid receptors, and A549, which down-regulates its expression, probed by the fluorescence intensity of Ag NCs. Importantly, Ag NCs along with PD synergistically induce prodrug mediated targeted cell death at a much reduced concentration of silver. Thus, theranostic nanocarriers have been developed offering the dual property of therapy and imaging based on the differential uptake.

Targeting Wnt Canonical Signaling by Recombinant sFRP1 Bound Luminescent Au-Nanocluster Embedded Nanoparticles in Cancer Theranostics.

Secreted frizzled-related protein 1 (SFRP1) is a natural blocker of the Wnt signaling pathway in normal adult cells but is epigenetically silenced in cancer cells leading to aberrant proliferation. In this study, we have reported novel composite nanoparticles fabricated with gold nanocluster embedded chitosan and alginate, bound to bacterially expressed human recombinant sFRP1. The Wnt pathway, which is upregulated in cancer, has been specifically targeted with the nanoparticles to achieve an antiproliferative effect on cancer cells, as evident from reduced levels of downstream molecules, namely, ß-catenin, cyclin D1, and survivin. The nanoparticles enabled sustained release of sFRP1 outside the cells, where it is functional. Moreover, remarkable luminescence properties of gold nanoclusters were exploited for binding, imaging, and tracking studies. Co-therapy of sFRP1-loaded nanoparticles with the drug cisplatin targeted two independent pathways to induce apoptosis, as documented by flow cytometry based assays. Overall, this nanosystem is promising for tracking, imaging, and targeting cancer signaling with therapeutic protein.