Immune Modulation and Metabolic Targeting Peptides: YEQDPWGVKWWY, CKGGRAKDC

The complexity and heterogeneity of the tumor microenvironment and the pathology of metabolic diseases, which profoundly influence therapeutic efficacy, pose major challenges. Precise targeting of specific cell types or tissues, especially immunomodulatory cells (e.g., tumor-promoting M2 macrophages) or metabolic core organs (e.g., fat tissue), has emerged as a key strategy to enhance efficacy and reduce systemic toxicity. Synthetic peptides are ideal vehicles for such precise interventions due to their structural designability, good tissue permeability, relatively low immunogenicity and ease of chemical modification. Among them, the peptide sequences YEQDPWGVKWWY (M2pep) and CKGGRAKDC represent outstanding advances in the fields of immune cell targeting (especially M2 macrophage) and fat tissue specific localization, respectively, and show broad prospects from basic mechanisms to therapeutic applications.

Targeting Immune Cells with Specific Peptides

Immune cells play a central role in maintaining homeostasis and responding to disease (e.g., cancer, autoimmune disease, infection). However, immune cell subpopulations function very differently, such as the tumor-promoting M2 subtype of tumor-associated macrophages (TAMs). Non-specific immunomodulation is often accompanied by off-target effects and limited efficacy. Selective targeting of specific immune cell subpopulations using specific peptides has become a breakthrough strategy for remodeling the immune microenvironment and achieving precise immune intervention. These peptides are usually obtained by mimicking natural ligands or screening phage display libraries, and can specifically bind to unique receptors or markers on the surface of target cells.

M2 Macrophage Targeting Peptide: YEQDPWGVKWWY Overview

M2 macrophages play a critical role in tumor progression, tissue repair (leading to fibrosis when abnormal) and immunosuppression. The peptide sequence YEQDPWGVKWWY, often referred to as M2pep, was obtained by phage display library screening and optimization, and exhibits a significant selective binding capacity to M2-type macrophages (including in vitro-induced M2 cells and in vivo tumor-associated macrophage TAMs), while binding weakly to M1-type or other immune cells. The molecular mechanism relies primarily on the interaction of specific amino acid residues in the peptide sequence (e.g., tryptophan W enrichment) with yet to be fully elucidated but relatively specific receptors or membrane proteins on the surface of M2 macrophages. This binding specificity makes M2pep an ideal "navigation head" for the precise delivery of therapeutic payloads (e.g., chemotherapeutic drugs, immunomodulators, siRNAs, imaging agents) to M2 macrophages. Functional studies have shown that M2pep itself does not directly kill cells, but its targeted delivery can effectively reprogram M2 macrophage phenotypes or induce apoptosis, laying the groundwork for subsequent therapies.

Therapeutic Potential in Tumor Immune Microenvironment

Based on the precision targeting properties of M2pep, it exhibits great therapeutic potential in improving the tumor immune microenvironment (TIME). The M2-type TAMs enriched in TIME are important drivers of immunosuppression and tumor progression. Coupling M2pep with antitumor drugs (e.g., adriamycin) to construct a targeted drug delivery system can significantly enhance drug enrichment in TAMs and effectively kill these tumor-promoting cells while reducing toxicity to normal tissues. More importantly, M2pep can be used as a carrier to deliver immune agonists (e.g., TLR ligands) or immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1 nanomaterials) to TAMs, which can directly reverse their immune-suppressing function, promote T-cell infiltration and activation, and transform "cold tumors" into "hot tumors". "hot tumors". In addition, using M2pep to deliver reporter genes or imaging agents, non-invasive and highly sensitive imaging of TAMs can be achieved, providing a powerful tool for tumor diagnosis, staging, prognosis assessment and treatment response monitoring. In vivo studies have demonstrated that M2pep-based strategies are effective in inhibiting growth and metastasis in a variety of hormonal tumor models (e.g., breast cancer, melanoma).

Fat Tissue Homing Peptide CKGGRAKDC and Its Applications

Fat tissue is not only an energy storage organ, but also an important endocrine and immunoregulatory organ, and its dysfunction is the core pathological basis of metabolic diseases such as obesity, type 2 diabetes mellitus and fatty liver. However, systemic administration is difficult to achieve effective concentrations in fat tissue and is prone to cause systemic side effects. The discovery of the peptide sequence CKGGRAKDC (usually cyclized with a disulfide bond as c[CKGGRAKDC], abbreviated as CKP) has revolutionized specific targeting in fat tissue. The peptide, obtained by in vivo phage display technology screening, has a highly selective binding ability to the white fat tissue (WAT) vascular endothelium, and its receptor has been identified as membrane-bound protein A2 (Annexin A2) and/or prolyl oligopeptidase (PROP), proteins that are highly expressed in the fat tissue vascular bed. This unique homing property makes it a powerful platform for enabling fat tissue-specific drug delivery and gene therapy.

Role in Metabolic Disease Treatment

CKGGRAKDC plays a key role in "precision guidance" in the treatment of metabolic diseases. Its core value lies in the efficient and selective enrichment of therapeutic molecules in fat tissue, significantly increasing local drug concentrations while reducing systemic exposure and side effects. In the treatment of obesity, CKP is widely used to deliver molecules that induce apoptosis or promote lipolysis in adipocytes. For example, coupling CKP with the pro-apoptotic peptide [D(KLAKLAK)2] selectively disrupts the vascular endothelium of fat tissue and blocks fat tissue neovascularization, thereby inhibiting fat accumulation and improving metabolic parameters. In the field of insulin resistance and type 2 diabetes, CKP can target delivery of insulin sensitizers (e.g., PPARγ agonist rosiglitazone derivatives) or anti-inflammatory agents (e.g., curcumin) to fat tissues, which can act directly on the core of inflammation, reduce fat tissue inflammation (e.g., lowering the levels of TNF-α, IL-6), and improve systemic insulin sensitivity. In non-alcoholic fatty liver disease (NAFLD/NASH), delivery of therapeutic nucleic acids (e.g., siRNAs targeting lipid metabolism genes) to fat tissue using CKP can modulate systemic lipid flow and indirectly ameliorate hepatic steatosis and inflammation.

Strategies for Fat Tissue-Specific Drug Delivery

Fat tissue-specific drug delivery strategies based on CKGGRAKDC have developed diverse and efficient systems. The most basic application is the construction of peptide-drug couplings (PDCs), which covalently attach small-molecule therapeutics to CKPs via cleavable or non-cleavable linkers. More sophisticated delivery systems utilize CKP-modified nanocarriers: smart nanodrugs are constructed by modifying CKP as a targeting ligand on the surface of liposomes, polymeric nanoparticles (PLGA, PEG-PLGA), dendrimers, or exosomes. These nanocarriers can encapsulate hydrophobic drugs, nucleic acid drugs (siRNA, mRNA), or protein/peptide drugs, and through CKP-mediated active targeting, enhance the specific adhesion of the carriers to the vascular endothelium of fat tissues and potentially facilitate trans-endothelial translocation, which ultimately leads to the release of therapeutic loads within adipocytes or stromal vascular fractions (SVFs). In addition, CKP has been used to construct gene therapy vectors targeting fat tissue (e.g., peptide-DNA complexes, peptide-modified adeno-associated virus AAV). Studies have shown that CKP-modified delivery systems can significantly improve the biodistribution and retention time of the load in fat tissue, several times or even tens of times more than the non-targeted control system, providing a powerful technical support for precision intervention in metabolic diseases.

Peptide-mediated precision targeting strategies provide powerful tools to overcome tissue-specific barriers in tumor immune microenvironment regulation and metabolic disease therapy. M2pep opens up a new pathway for remodeling the immunosuppressive tumor microenvironment and enhancing the anti-tumor immune response by selectively binding to M2 macrophages. On the other hand, the unique homing ability of CKGGRAKDC (CKP) to the vascular endothelium of fat tissues has greatly contributed to the development of targeted therapies for metabolic diseases, enabling efficient enrichment and localization of therapeutic molecules in fat tissues. These two classes of peptides represent cutting-edge directions at the intersection of biomaterials and therapeutics. Future studies should deeply analyze their precise action receptors and intracellular signaling pathways, optimize their pharmacokinetic properties (e.g., stability, half-life), explore more efficient and safe coupling and delivery strategies, and promote their translation to the clinic. Interdisciplinary collaboration will further unleash the potential of these targeted peptides in the field of immuno-metabolic regulation and provide innovative solutions for precision medicine of cancer and metabolic diseases.

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