Bi-Functional Topospecific Nanoparticles to Promote Immune-Tumor Cell Engagement as A New Immunotherapeutic Strategy

Sep 30, 2026

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Cancer immunotherapy leverages the immune system to eliminate tumors, but effective cytotoxic T cell activity requires reliable physical contact and communication with cancer cells. Immune escape mechanisms often disrupt this engagement, limiting responses and increasing risk of adverse effects. This work develops Janus mesoporous silica-Au nanoparticles (J-pHLIP-PD1) enabling simultaneous binding to tumor cells and T cells via orthogonal functional surfaces, triggering immune-synapse-like structures, immunogenic cell death signatures, reduced viability in vitro, and improved outcomes in an in vivo metastatic melanoma model.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages19

Reading Time48 min

AccessFree to download

Introduction

Rationale: immune escape and synapse disruption

Nanoplatform design and dual targeting concept

In vitro engagement and immunogenic cell death

In vivo metastatic melanoma efficacy

Overall significance as an immune-engaging strategy

RESEARCH ARTICLE [www.advmat.de](www.advmat.de) Bi-Functional Topospeciﬁc Nanoparticles to Promote Immune-Tumor Cell Engagement as A New Immunotherapeutic Strategy Alba Ortuño-Bernal, Sandra Clara-Trujillo, Elena Lucena-Sánchez, Francisco J. Hicke, Andrea Escudero, Sandra Pradana-López, Nelia Jiménez-Alduan, Paula Díez, Alba García-Fernández,* and Ramón Martínez-Máñez* Cancer immunotherapy has emerged as a promising alternative approach, enabling the body’s immune system to ﬁght cancer. Cytotoxic T cells play a pivotal role in recognizing and eliminating tumor cells, and their eﬀectiveness relies on establishing a physical interaction and eﬃcient communication with cancer cells. However, this communication is often disrupted by immune escape mechanisms, allowing cancer progression. A versatile nanoplatform is developed to restore cellular connection using Janus mesoporous silica-Au nanoparticle (J-pHLIP-PD1), including speciﬁc binding sites on opposite faces for simultaneous binding to cancer cells and immune cells. The two diﬀerential surfaces on the nanoparticle allow orthogonal functionalization with the anti-PD-1 antibody that interacts with the PD-1 receptor in cytotoxic T cells on the gold face and the pH Low Insertion Peptide (pHLIP), which undergoes speciﬁc insertion into the tumor cell membrane on the silica face. J-pHLIP-PD1 nanoparticles eﬀectively bind the surface of tumor cells and capture T cells, facilitating the formation of immune synapse-like structures that lead to reduced cancer cell viability in vitro, associated with immunogenic cell death signatures. The therapeutic potential of J-pHLIP-PD1 is also demonstrated in an in vivo metastatic melanoma model, where treatment with J-pHLIP-PD1 produces a signiﬁcant decrease in metastatic burden and increases T cell presence. The Janus nanosystem represents an attractive platform that expands the toolbox of immune-engaging strategies, oﬀeringa ﬂexible alternative to conventional immunotherapies that link immune and tumor cells, restoring cell–cell communication for cancer elimination. 1. Introduction The immune system’s primary task is to distinguish the antigens that belong to the body from those of foreign or damaged cells, to eliminate them. [1] One example is tumorigenic mutant cells whose elimination involves several types of immune cells that coordinate their actions and prevent cancer development. However, this process is sometimes defective, and the immune system fails in the removal, allowing the tumor to progress. [2,3] Recently, cancer immunotherapy has become a potent strategy to take advantage of the immune system’s ability to identify and eliminate cancer cells. Compared to conventional therapies (such as chemotherapy, radiotherapy, and surgery), these treatments have signiﬁcantly improved patients’ quality of life and survival rates. [4,5] However, despite the progress with cancer nanovaccines,[6] checkpoint therapies,[7] and T cell therapy (i.e. CAR-T)[8] the translation into patients remains challenging and raises concerns related to low response and adverse eﬀects. [9–11] In most cases, tumors escape from the immune system is due to the disruption of immune cell-tumor A. Ortuño-Bernal, S. Clara-Trujillo, E. Lucena-Sánchez, F. J. Hicke, A. Escudero, S. Pradana-López, N. Jiménez-Alduan, P. Díez, A. García-Fernández, R. Martínez-Máñez Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM) Universitat de València–Universitat Politècnica de València Camino de Vera s/n, Valencia 46022, Spain E-mail: [algarfe4@upvnet.upv.es](algarfe4@upvnet.upv.es); [rmaez@qim.upv.es](rmaez@qim.upv.es) The ORCID identiﬁcation number(s) for the author(s) of this article can be found under [https://doi.org/10.1002/adma.202418838](https://doi.org/10.1002/adma.202418838)[ ](https://doi.org/10.1002/adma.202418838)© 2025 The Author(s). Advanced Materials published by Wiley-VCH GmbH. This is an ope

FAQs

What problem does the study address in cancer immunotherapy?

The study addresses impaired physical interaction and communication between cytotoxic T cells and tumor cells due to immune escape mechanisms.

How do J-pHLIP-PD1 nanoparticles support tumor-immune engagement?

They use a Janus design with different functionalization on opposite faces to bind both cancer cells and immune cells, promoting immune synapse-like structures.

What evidence is provided for therapeutic potential?

In vitro results show reduced tumor cell viability with immunogenic cell death signatures, and in vivo treatment in metastatic melanoma models decreases metastatic burden and increases T cell presence.

Sep 30, 2026

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