Biomaterial-Enabled In vivo T Cell Engineering: A New Paradigm for Cell Therapy

Summary:

T cell therapies have transformed treatment for previously intractable diseases. However, their full potential remains constrained by reliance on ex vivo cell manipulations, which reduces cell quality, drives up manufacturing costs, and requires lengthy production times, ultimately reducing treatment efficacy and restricting patient access. Recent breakthroughs in biomaterials science, immunoengineering, and genetic editing have catalyzed a paradigm shift toward direct in vivo immune cell engineering using instructive biomaterials. These emerging strategies circumvent traditional limitations by dramatically reducing costs, eliminating manufacturing delays, and improving therapeutic outcomes through preservation of native cell states and functions. Key technological advances include highly specific targeted biomaterial-assisted gene delivery and instructive biomaterials that establish controlled microenvironments for precise immune cell programming and modulation. In this Perspective, we examine how biomaterials are redefining T cell therapies across a range of pathological contexts, from cancer to autoimmune disease. We analyze emerging breakthrough platforms, highlight their therapeutic potential, and discuss key challenges limiting clinical adoption. Looking ahead, we provide insights into future developments that could democratize access to these transformative immunotherapies.

(3) an eTOC blurb

Biomaterials are evolving from passive cell delivery vehicles into active regulators of immune cell fate and function, enabling cell engineering directly within the body. This perspective highlights the evolution of bulk and injectable biomaterials into multifunctional platforms that can integrate cell recruitment, manufacturing, reprogramming, and delivery while addressing key barriers of cell therapies. By reshaping how therapeutic cells are generated and controlled, these emerging platforms have the potential to improve safety, scalability, and accessibility.

Shifting paradigms: The promise of biomaterials for in vivo cell reprogramming

T cell therapies, including chimeric antigen receptor (CAR)-T cell therapies, have demonstrated transformative clinical successes, achieving unprecedented remission rates in patients with otherwise intractable hematologic malignancies ¹. However, despite their remarkable clinical success, the broader impact of these therapies is constrained by substantial manufacturing challenges. The current therapies rely on extensive ex vivo cell manipulation that requires specialized GMP facilities, stringent quality control processes, and individualized manufacturing workflows, collectively driving treatment costs to hundreds of thousands of dollars per patient. These processes require centralized manufacturing and intricate supply chains imposing logistical complexities that delay the treatment for patients with advancing diseases ^2,3. Moreover, existing production methods lack scalability and create differentiated cell products with limited proliferative capacity, persistence, and antitumor potency, leading to persistent bottlenecks even as clinical demand continues to grow.

These limitations have catalyzed a paradigm shift toward in vivo cell therapies, where immune cells are reprogrammed directly within their native tissue environments without the need for labor-intensive and time-consuming external manipulation ^4,5. By harnessing endogenous cell populations, these strategies forego ex vivo cell isolation, reprogramming, expansion, and reinfusion, bypassing major manufacturing, logistical, and access-related constraints. Moreover, in vivo reprogramming offers the potential for rapid, on-demand treatment while preserving natural cellular phenotypes and functions, significantly reducing treatment delays and ex vivo culture induced alterations that can compromise therapeutic outcomes ⁶. In vivo cell reprogramming, often through direct injection of viral vectors, has gained significant traction due to multiple ongoing clinical trials ^4,7,8. However, this approach faces fundamental barriers for widespread adoption. The biodistribution of systemically infused viral vectors is often poorly controlled, resulting in inefficient delivery to target immune cells. Additionally, widespread, nonspecific systemic exposure increases the risk of off-target gene integration, insertional mutagenesis, and unintended immune activation, raising safety concerns. The therapeutic efficacy of this approach can be hampered by immunogenic responses to the vectors and their rapid clearance, which can limit effective dosing, reduce transduction efficiency, and prevent repeat dosing. Furthermore, manufacturing of clinical-grade vectors remains costly and resource-intensive, and stringent regulatory requirements further limit its scalability and widespread clinical applications ^9,10. Thus, while in vivo reprogramming could broaden treatment eligibility by overcoming biological and logistical barriers, its full therapeutic potential remains limited by the lack of control over where, when, and how immune cells encounter genetic cargo and activating signals ¹¹. These constraints create a compelling opportunity for biomaterial-based platforms that can localize genetic modifiers, present stimulatory ligands, and create engineered immune niches that recapitulate key aspects of lymphoid microenvironments.

Biomaterials as Architects of Immunity

Biomaterials have long been integral to immune cell engineering approaches, providing tunable physical, mechanical, and chemical properties that enable broad use in ex vivo applications including cell culture substrates, isolation platforms, activation systems, and controlled differentiation environments ¹². From the earliest days of T cell culture, artificial substrates, polymer-coated vessels, and microcarrier systems were used to provide adhesion and mechanical support for lymphocyte expansion, enabling reliable propagation of otherwise suspension-prone cells. As adoptive cell therapies matured, biomaterials evolved from passive cultureware into active regulators of immune cell fate. Engineered surfaces presenting anti-CD3, anti-CD28, and other stimulatory ligands replaced soluble activation, allowing precise control over receptor clustering, signal strength, and activation kinetics. By providing defined and reproducible microenvironments ¹³, biomaterials-based systems streamlined immune cell engineering and improved functional outcomes relative to conventional culture methods. Beyond improving ex vivo cell expansion and activation, biomaterials gradually became tools for shaping how therapeutic immune cells survive and function after they are delivered in vivo. Biomaterials have been engineered as local or systemic delivery depots that physically anchor therapeutic cells, shield them from hostile tissue environments, and supply supportive cues that enhance their persistence and function after transfer ^14,15.

In this Perspective, we highlight recent advances in using biomaterials as fully in vivo modulators of T cell function and genetic reprogramming—platforms that move beyond simple delivery vehicles to become active, programmable immunomodulators. These systems localize genetic cargo, activation signals, and metabolic support within defined tissue microenvironments, enabling immune cells to be recruited, stimulated, engineered, expanded, and released entirely within the body. By integrating spatial control, sustained signaling, and cell-specific targeting, biomaterials provide a level of orchestration that systemic viral vectors can’t achieve alone. Across bulk scaffolds, injectable matrices, and nanoparticle platforms, these approaches establish a new paradigm for in vivo immunotherapy in which immune cell fate is shaped by the context of engineered material rather than ex vivo manufacturing pipelines (Figure 1). In the sections that follow, we examine how these instructive biomaterial platforms are redefining T cell therapy, compare their emerging architectures, and discuss the opportunities and challenges they present for translating in vivo immune engineering to the clinic.

Figure 1.

A) Shifting paradigms: from ex vivo to in vivo manufacturing. Traditional CAR T cell manufacturing relies on costly and time-intensive ex vivo processes which can lead to dysfunctional CAR T cell products, whereas the newer in vivo approach involves direct systemic administration of CAR vectors. B) Implantable and injectable biomaterials are emerging tools to streamline immune cell engineering entirely in vivo.

Localized Bulk Biomaterials for Immune Programming

Bulk biomaterials are implantable or injectable matrices that enable direct control over the spatial, mechanical, and biochemical context in which immune cells operate. Rather than relying on systemic distribution, these materials establish localized microenvironments that concentrate therapeutic signals and cells at defined anatomical sites, allow stochastic encounters, and recapitulate key features of native lymphoid tissues. This localized control has made them an important foundation for in vivo immune engineering strategies aimed at directing immune responses in cancer, autoimmune disease, and tissue repair. To date, they have been used widely as cell delivery vehicles, where their porous architecture has enabled cellular survival, motility, and egress. However, more recently, via tuning of their material, physical, chemical, and biological properties, a shift has occurred towards using these biomaterials to actively recruit, retain, and instruct immune cells in situ. In this capacity, bulk biomaterials function not merely as delivery vehicles, but as synthetic immune niches that orchestrate immune cell fate by co-localizing cells with activating cues, genetic payloads, and supportive signals in a spatially and temporally controlled manner. This capability has positioned bulk biomaterials as a foundational platform for in vivo immune engineering, enabling precise, localized, and programmable modulation of immune responses across cancer, autoimmunity, and regenerative applications (Figure 2).

Figure 2.

Bulk biomaterials for T cell modulation. The physical, chemical, and biological parameters of these biomaterials can be carefully tuned to provide control over immune cell recruitment, activation, reprogramming, proliferation and release.

A biomaterial’s ability to shape immune responses is strongly influenced by its physical and chemical properties, including material composition, porosity, surface charge, stiffness, and viscoelasticity. Naturally derived biomaterials like alginate and collagen are widely used for their biocompatibility and established clinical precedent^16–18, whereas synthetic materials like PEG-based platforms offer high modularity and chemical tunability^{19, 20}. Scaffold macroporosity supports immune cell infiltration and retention, allowing localized in situ reprogramming¹⁹. Porous architecture also facilitates cell transfection and transduction by increasing cell-vector interactions through improved transport and colocalization within the scaffold^21–23. Beyond transport considerations, immune cells are responsive to biophysical cues such as charge, stiffness, and viscoelasticity, which regulate their migration²⁴, activation ²⁵, and differentiation²⁶. Tuning substrate charge can amplify TCR signaling and proliferation-related transcription factor activity, leading to improved antitumor efficacy in vivo¹⁶. Charge can also be manipulated to functionalize biomaterials, for example by coating macroporous scaffolds with positively charged poly-L-lysine to enable immobilization of negatively charged lentiviral vectors¹⁹. Mechanical properties similarly regulate T cell function¹⁷. T cells sense substrate mechanics through integrins (e.g. LFA-1) and the TCR, coupling extracellular forces to cytoskeletal remodeling and potentially downstream signaling pathways such as RhoA/ROCK and YAP/TAZ¹⁸. Substrate stiffness can promote T cell activation and, on polyacrylamide gels, has even been shown to induce Tregs by increasing oxidative phosphorylation, highlighting that distinct mechanical regimes may favor divergent therapeutic outcomes¹⁹. Although these effects have been primarily explored in vitro, they remain important considerations for in vivo design. Notably, tuning material viscoelasticity can generate injectable, in situ-forming scaffolds that flow during administration but rapidly recover structure after placement.^20,21 These injectable systems not only simplify administration but also can enable immune cell spreading, motility, and mechanosensitive signaling programs that are limited in purely elastic networks.

In addition to material properties, bulk biomaterials provide a unique opportunity to encapsulate and deliver one or more biochemical signals enabling direct instruction of immune cell behavior. By localizing immunomodulatory signals, these materials create engineered immune niches that can recruit defined immune populations. Scaffolds and hydrogels designed for immune modulation have been loaded with potent chemokines such as CXCL10, CXCL11, and CCL21 to establish chemokine gradients that prompt migration of naïve, effector, or memory T cells in a way that mimics native signaling pathways^20–22 In these examples, the material composition and charge allows electrostatic interactions between biomaterials and chemokines for effective release kinetics, and in turn, T cell recruitment. Alongside chemokine delivery, controlled cytokine presentation represents a central strategy by which instructive biomaterials enhance T cell expansion, functionality, and persistence. Cytokines such as IL-2, IL-7, IL-15, and IL-21 regulate T cell proliferation, survival, and memory formation, but their systemic administration is limited by short half-life and dose-limiting toxicities. Scaffold or hydrogel-mediated presentation of IL-2 supports robust T cell expansion and effector function ²³ as well as reduces off-target activation of regulatory T cells ²⁴. Similarly, delivery of IL-7 and IL-15 promotes memory differentiation and long-term persistence, addressing durability limitations of many immunotherapies ²⁵. Overall, biomaterial-based cytokine delivery decouples immunostimulatory efficacy from systemic toxicity, enabling precise control over T cell fate and function in situ.

Instructive biomaterials can equip immune cells to navigate across tissue barriers and support combinatorial interventions that achieve synergistic immune modulation^26–28. This coordinated presentation of costimulatory antibodies, checkpoint inhibitors, and metabolic regulators enhances T cell trafficking through dense or immunosuppressive tissues, promotes memory formation, and sustains long-term effector function and survival, while maintaining precise spatial control over multiple therapeutic cues^21,29, overcoming key limitations of single-agent or systemic therapies. Instructive biomaterials incorporating and releasing growth factors like GM-CSF promote recruitment, differentiation, and activation of dendritic cells, enhancing antigen presentation and priming of tumor-specific T cells. In parallel, local delivery of chemotherapeutic agents from biomaterials induce immunogenic cell death, increase tumor inflammation, and amplify endogenous antitumor immune responses ³⁰. Similarly, hydrogels co-delivering VEGFR inhibitors and 4-1BB agonistic antibodies have demonstrated the ability to simultaneously normalize tumor vasculature, alleviate hypoxia, and reverse T cell exhaustion, resulting in more durable and potent antitumor immunity²⁹. Importantly, instructive biomaterial platforms are not limited to immune activation but can also be rationally designed to promote immune tolerance. Scaffolds loaded with chemokines and metabolic modulators such as eliglustat have been shown to recruit T cells and bias their differentiation toward regulatory T cell phenotypes²¹, whereas scaffolds combining TGF-β blockade with chemokines and agonistic antibodies enabled local depletion of regulatory T cells while simultaneously recruiting, activating, and expanding effector and memory T cell populations ²².

Beyond the encapsulation and release of biological molecules, bulk materials can be chemically functionalized to present biological cues to cells in a spatiotemporal manner, simulating natural immune microenvironments ³¹. A growing body of work is highlighting the ability of instructive biomaterial platforms to mimic lymphoid tissue by presenting agonistic antibodies like anti-CD3 and anti-CD28 in a sustained and spatial manner. Concurrent presentation of these cues allows T cell activation, stimulation and proliferation necessary for T cells’ effector function. In these approaches, materials and biologics are often chemically functionalized to react with each other using orthogonal click reactions or thiol-based conjugations ^{22,26,32–34}. This tunable chemistry allows incorporation of several different biologics in the biomaterial platform to provide the modularity and flexibility necessary for immune cell activation, reprogramming, expansion, and eventual release entirely in vivo. More recently, in situ forming injectable scaffolds have been designed to enhance the persistence and function of pre-administered CAR T cells. Incorporation of anti-CD3, anti-CD28 ligands by means of biotin–streptavidin linkages and IL2 coating on the mesoporous silica rods allowed infiltration of T cells in mice previously treated with conventional therapies³⁵.

Interestingly, many of these platforms provide integrated all-in-one systems that can orchestrate many sequential steps in T cell immune modulation in vivo. These systems have been designed to simultaneously recruit, activate, genetically modify, and direct the fate of T cells by incorporating combinations of chemokines, cytokines, costimulatory antibodies, checkpoint modulators, microparticles, and gene-delivery vectors. A defining feature of these integrated systems is the ability to independently tune multiple signal axes within the same material to tune the activation thresholds, cytokine release profiles, cell expansion, and release rate as well as the level of differentiation required. In some platforms, transgene-encoding viral or non-viral vectors are embedded directly within scaffolds or hydrogels, enabling localized T cell activation alongside in situ genetic reprogramming ^26,32. In others, activation cues are combined with recruitment signals and/or viral vectors to allow instructive biomaterials to mimic aspects of natural lymphoid microenvironments while offering levels of spatial and temporal control ²⁰. However, it is important to consider that increased incorporation of immunomodulatory features introduces increased manufacturing complexities and safety concerns that may limit translation. Each component must be rigorously validated and tested, which will be costly and time-intensive in a large-scale GMP-compliant setting. Furthermore, since these biomaterials are macroscopic 3D structures, there is limited ability to tune the dose for each patient. Thus, while bulk biomaterials offer a unique platform for localized in vivo immune programming, their clinical translation will require rigorous attention to scalability, safety, and regulatory complexity.

Systemically Delivered Biomaterials for Immune Programming

Injectable and particle-based biomaterials are redefining in vivo immune engineering by offering versatile, scalable, and systemically deployable platforms that extend immunomodulation beyond localized material sites. These include 1) lipid nanoparticles (LNPs), which are synthetic lipid-based nanocarriers optimized for nucleic acid delivery ³⁶; 2) polymeric carriers, which use biodegradable polymers to condense, protect, and release genetic or immunomodulatory payloads ^5,37; and 3) vesicle-based formulations, which include cell-derived or biomimetic lipid vesicles that preserve membrane architecture and protein presentation ³⁸. Tuning their physicochemical properties, like particle size, surface charge, surface conjugation, and degradation kinetics ^39,40, can influence their circulation, biodistribution, and cellular uptake. Accordingly, nanoparticle design determines not only where particles accumulate, but also which immune cells engage them and whether delivered cargo reaches functionally relevant intracellular compartments. This broadens the scope of in vivo immunotherapy beyond localized biomaterial depots to systematically deployable immune programming platforms (Figure 3).

Figure 3.

Injectable biomaterials for T cell modulation. An injectable platform (nanoparticle, vesicle, cell backpacks) can be modified to present or release immunomodulatory cues that can influence T cell activation, reprogramming and differentiation.

Lipid nanoparticles have been particularly transformative for in vivo immune cell reprogramming due to their modular composition, enabling precise delivery to target cells, intracellular trafficking, and controlled reprogramming. Typical LNP formulation contains ionizable lipids for nucleic acid complexation, helper lipids for structural stability, and PEG-lipids to regulate size, circulation, and serum stability. Importantly, LNPs can be further functionalized with targeting ligands, enabling selective engagement with defined T cell subsets and reducing off-target delivery ⁴⁰. Leveraging these design principles, recent studies have demonstrated efficient in vivo generation of functional CAR T cells through delivery of CAR-encoding mRNA or DNA to circulating lymphocytes. Antibody-decorated LNPs targeting pan-T cell markers (e.g., CD3^8,41 or CD5⁵) or subset-specific markers (e.g., CD4⁴² or CD8^43,44) have been used to couple receptor-mediated uptake with transient T cell activation, which increases the T cell permissiveness to transfection with the CAR. Thus, this strategy simultaneously confines CAR expression to T cells while increasing the population of successfully transfected cells. In many cases, receptor engagement does more than improve binding specificity. Antibody ligation of surface markers such as CD3 can transiently activate T cells, promoting a cellular state that is more permissive to nanoparticle uptake and subsequent genetic modification. This dual role may be particularly important for in vivo engineering strategies, as activation not only supports T cell proliferation and functional programming but can also enhance transfection efficiency, potentially contributing to improved responses upon repeated dosing, as observed in recent targeted LNP studies¹¹.

These advancements have led to multiple LNP-based platforms being explored in clinical trials for cancer and autoimmune indications (Table 1) ^11,45. In particular, CD3-targeted LNPs delivering anti-CD19 CAR mRNA produced functional CAR T cells in situ that mediated tumor regression in mouse models without any ex vivo cell manipulation.⁵ Similarly, CD8-targeted LNPs encoding anti-CD19 CARs achieved selective reprogramming of CD8+ T cells in vivo, generating CAR T populations that led to effective B cell aplasia in humanized mice⁴³ as well as achieving complete B cell depletion and clinical remission in patients with refractory systemic lupus erythematosus (SLE) ⁴⁵. Beyond autoimmune diseases, this targeting approach has been adapted for tissue repair where LNPs conjugated with cardiotropic peptides delivered CAR constructs targeting activated fibroblasts (FAP) in murine hearts post-myocardial infarction, restoring ejection fraction to levels comparable to mice without myocardial infarction. ⁴⁶ However, because many LNP-delivered payloads are non-integrating, repeated dosing or combination strategies may be required when persistent cell expansion or long-term tumor surveillance is necessary.

Table 1:

Ongoing clinical trials and startup landscape

Startup/company	Biomaterial	Cargo	Product	Application	Phase	Clinical trial
Capstan	CD8-tLNP	mRNA	CPTX2309	autoimmune diseases	clinical	NCT06917742
Shenzen MagicRNA	CD8-tLNPs	mRNA	HN2301	autoimmune (R/R) systemic lupus erythematosus (SLE	clinical	NCT06801119
Immorna Biotherapeutics	LNPs	mRNA	JCXH-213	hematological cancers (R/R B cell NHL)	clinical	NCT06618313
Starna Therapeutics	LNPs	mRNA	STR-P004	R/R B cell non-Hodgkin lymphoma	clinical	NCT07003178
Strand Therapeutics	LNP	circRNA	STX-001	Solid tumors	preclinical	NCT06249048
Startup/company	Biomaterial	Cargo	Product	Application	Phase	ref
Aera Therapeutics	LNPs	mRNA	AERA-109	autoimmune diseases	preclinical	ASGCT – 770, 61
Sanofi	tLNPs	mRNA		hematological cancers	preclinical	ASGCT – 260, 62
NanoCell Therapeutics	tLNPs	minicircle DNA and transposase mRNA	NCtx	hematological cancers	preclinical	ASGCT–213, 44
Orna Therapeutics	LNPs	(circular RNA)	oRNA®	hematological cancers and autoimmune diseases	preclinical	63
Tessera Therapeutics	tLNP	RNA	Gene Writers™	cancers and autoimmune	preclinical	ASGCT-153, 64
Ensoma	virus-like particles (VLPs)	Sleeping Beauty transposase	SB100X	solid tumors	preclinical	ASGCT–1783, 65
Azalea Therapeutics	enveloped delivery vehicle (EDV)	CRISPR–Cas9 ribonucleoprote ins		B cell malignancies and autoimmune diseases	preclinical	ASGCT–151, 66
Nitto Denko Corporation	anti-CD8 VHH-t LNP	mRNA		hematological cancers	preclinical	ASGCT–665, 67
Sail Biomedicine	tLNP	endlessRNA	SAIL-0804	autoimmune diseases	preclinical	ASGCT–774, 68
Grit Biotechnology	tLNP	mRNA	GT801	autoimmune diseases,hematological cancers	preclinical	ASGCT–1282, 69
Orbital Therapeutics / Bristol Myers Squibb	tLNP	circRNA	OTX-201	autoimmune diseases	preclinical	70
Aanastra	Peptide NPs	mRNA		Hematological cancers and autoimmune diseases	preclinical	ASGCT–1283, 71
Velvet Therapeutics	Polymer NPs	DNA		Solid and liquid tumors	preclinical	ASGCT – 699, 72
RiboX Therapeutics	tLNP	circRNA		hematologic cancers and autoimmune diseases	preclinical	ASGCT–1762, 73

In contrast to lipid-based nanoparticles, which are predominantly optimized for nucleic acid delivery and therefore must balance circulation stability with rapid endosomal destabilization, polymeric nanocarriers are not constrained by these requirements and offer greater design flexibility in structural stability, degradation kinetics, and signal persistence, extending their utility beyond gene delivery alone. These platforms can be engineered to coordinate antigen presentation, costimulatory or coinhibitory signaling, and immunomodulatory drug release within a single construct, enabling precise control over immune cell fate. For example, tolerogenic artificial antigen-presenting nanoparticles (PLGA- and PBAE-based) displaying peptide-MHC complexes and co-inhibitory signals successfully induced antigen-specific regulatory T cells in preclinical models highlighting their potential to treat autoimmune diseases like type 1 diabetes and multiple sclerosis ⁴⁷. Similarly, a self-assembling nanoparticle formed by chemical modification of an immunosuppressive mTOR inhibitor (PP242) has demonstrated preferential accumulation in macrophages when delivered systemically and suppressed T cell function, significantly prolonging graft survival in a preclinical model of heart transplantation ⁴⁸.

Vesicle-based formulations provide an alternative, biomimetic approach to in vivo immune engineering that leverages natural mechanisms of intracellular communications. This class includes extracellular vesicles (EVs), such as exosomes, engineered cell-derived nanovesicles that recapitulate cell membranes at scale; and virus-mimetic fusogenic vesicles that harness viral-like membrane fusion for efficient cytosolic delivery. Because these vesicles inherit membrane lipids and proteins that evolved for intercellular communication, they may evade some synthetic uptake barriers and promote fusion-mediated cytosolic delivery, reducing reliance on endosomal escape, which is a common bottleneck for many nanoparticle systems. Notably, fusogenic nanovesicles displaying anti-CD3 single-chain variable fragments and carrying anti-CD19 CAR generate functional CAR T cells in vivo by direct fusion with T cell membranes and produced antitumor activity in lymphoma models while limiting systemic toxicity ³⁸.

Beyond intracellular delivery, “cell backpacks” offer a complementary immune engineering strategy in which nanoparticles are stably tethered to immune cell surfaces, converting them into targeted drug depots. In these systems, cytokine-, drug-, or enzyme-loaded nanogels are chemically conjugated to cell membranes using reactive chemistries like NHS-amine coupling or maleimide-thiol reactions ⁴⁹ enabling stable surface tethering without internalization. This preserves intracellular function while spatially decoupling cargo delivery from endocytic trafficking, allowing immune cells to act as self-guided carriers while preserving the payload for localized extracellular release. The backpacked cargo is often selected to provide sustained, localized immunomodulation: for instance, IL-2–loaded nanogels attached to regulatory or effector T cells can release cytokine in response to TCR signaling or microenvironmental cues, delivering autocrine stimulation at antigen-engaged sites while minimizing systemic toxicity ⁵⁰. Enzyme-loaded nanogels carrying hyaluronidase have similarly been “backpacked” onto CAR T cells to locally degrade tumor extracellular matrices, improving infiltration and efficacy in solid tumors ⁵¹. Surface-tethered nanoparticles have also delivered small-molecule immunomodulators, including combinations such as IL-2 with β-cell regenerative agents, to improve Treg stability and fitness in vivo, highlighting the potential of this approach for tolerance induction ⁵².

Collectively, injectable biomaterials should be selected according to biological objective: LNPs for rapid transient genetic programming, polymeric systems for multicomponent or sustained signaling, vesicle-based systems for biomimetic cytosolic delivery, and cell-associated carriers for spatially guided local modulation. Together, injectable biomaterials represent a rapidly advancing strategy for in vivo immune engineering, offering scalable, modular platforms capable of integrating transient genetic reprogramming, immune targeting, cytokine delivery, and small-molecule modulation within a single system. Compared with bulk biomaterials, these systems are generally more compatible with systemic administration, repeat dosing, dose titration, and standardized manufacturing windows. These materials enable levels of combinatorial and spatial control that are difficult to achieve with conventional cell manufacturing, while retaining favorable safety profiles through non-integrating, self-limiting payloads such as mRNA. However, these advantages are balanced by reduced spatial control, dependence on biodistribution and target-cell uptake, and the challenge of coordinating multiple biological signals within a single transient delivery event. Their clinical translation also remains limited by their inherently transient nature of these payloads, which often necessitates repeated dosing. Additionally, formulating and manufacturing nanoparticles capable of delivering more complex cargo, such as larger proteins, multiple genes, or combinatorial immunomodulators is challenging. Emerging preclinical studies in context-responsive and cell-associated particulate systems, such as inflammation- or antigen-triggered nanoparticles and surface-tethered “cell backpacks,” provide avenues to address these limitations by improving persistence, local delivery, and functional synergy. Collectively, while nanoparticle-based biomaterials offer layers of tunability for immune cell programming, their translation will require careful balance of efficacy, safety, and durability, highlighting the need for continued optimization and evaluation in relevant disease models.

Existing Barriers and Future Directions

A central challenge for both bulk and nanoscale biomaterial-based immune engineering is the host immune response, arising from both the biomaterials themselves and incorporated cargoes such as nucleic acids, proteins, or viral vectors. In bulk biomaterial scaffolds, host recognition of implanted materials can trigger a foreign body response characterized by protein adsorption, complement activation, innate immune cell recruitment, and fibrotic encapsulation. Though extensive strategies have been developed to mitigate these inflammatory responses,⁵³ these processes can alter local immune signaling and compromise therapeutic efficacy not only by impeding cell infiltration or egress but also by shifting immune phenotypes unfavorably. In nanoparticle systems, the main challenge related to the host immune response is rapid particle clearance and inactivation rather than localized tissue inflammation. Even materials historically considered biologically inert, such as PEG, are now known to elicit anti-polymer immune responses that accelerate clearance, alter pharmacokinetics, and reduce efficacy upon repeat dosing⁵⁴. Additionally, myeloid cells are naturally predisposed to particle internalization through endocytosis, while T cells are less permissive to particulate internalization. This mismatch reduces the efficiency of on-target T cell engineering while increasing risks of off-target immune activation, inflammatory cytokine production, and unintended genetic modification of phagocytic cells. Addressing these responses requires rational tuning of chemistry, surface functionality, degradation kinetics, and mechanical features to minimize recognition by the immune system while preserving therapeutic function. These can include the incorporation of “stealth” coatings like zwitterionic polymers to add a steric barrier preventing protein adsorption or CD-47 mimicking peptides to present “don’t eat me” signals to phagocytic cells⁵⁵. Accordingly, complementary strategies that incorporate computational modelling to predict immune response are increasingly important for de-risking material design ⁵⁶.

Achieving precise control over T cell programming often requires complex biomaterial systems, which creates a major challenge for manufacturing. Systems incorporating increasing numbers of immunomodulatory cues can provide greater spatial and biological control over immune cell fate, but this added complexity also increases manufacturing burden, regulatory hurdles, and challenges in mechanistic interpretation. Multifunctional platforms often require extensive validation of each component, their interactions, and batch-to-batch consistency under GMP-compliant manufacturing. In addition to manufacturing complexity, these systems must also coordinate the kinetics of distinct biological signals, for example, providing T cell activation prior to gene delivery. In contrast, due to their modularity, systemically administered nanoparticle platforms are generally easier to manufacture and standardize but often sacrifice control over cell fate and rely heavily on biodistribution and target cell uptake. Across all biomaterial technologies, even small variations in synthesis, cargo loading, or storage can substantially alter therapeutic performance. Furthermore, limited shelf life, specialized handling, or bedside preparation may further complicate clinical implementation. These constraints may help explain why many systems demonstrating strong preclinical biodistribution or gene-delivery metrics have yet to translate into consistent therapeutic responses in clinically relevant disease settings. Collectively, these considerations underscore the need for multilayered control over vector localization, activity, and persistence to enable safe translation of biomaterial-enabled in vivo immune engineering.

Beyond manufacturing considerations, biomaterial-enabled immunotherapies raise unique regulatory challenges due to their hybrid nature. For example, bulk hydrogels incorporating cytokines, viral vectors, or living cells blur traditional boundaries between biologics, devices and gene therapies, complicating regulatory classification and slowing clinical translation despite strong preclinical performance⁵⁷. While nanoparticle systems have successfully reached the clinic for vaccine and drug delivery, biomaterial-enabled immune engineering introduces additional layers of complexity because these platforms interact with living immune cells that can proliferate, migrate, and persist long after the material itself has degraded. As a result, therapeutic exposure is not determined solely by administered material dose or clearance kinetics, but also by biological amplification through immune activation and cell expansion. This makes the effective in vivo dose highly context-dependent and difficult to predict. Moreover, many biologics and reagents used for immune cell manipulation were originally developed and optimized for ex vivo use, and translating these components into in vivo biomaterial systems introduces additional challenges related to safety, biodistribution, toxicity, and regulatory approval. In many cases, individual components such as IL-2⁵⁸ or LNP mRNAs⁵⁹ may have prior clinical precedent, whereas others, including antibodies, gene-delivery vectors, or synthetic nucleic acids, may be administered in vivo for the first time.

As in vivo immune engineering platforms mature, a central distinction has emerged between the durable gene delivery enabled by viral vectors and the flexibility and control offered by non-viral nanoparticle systems. Viral vectors remain the gold standard for efficient and durable genetic modification in vitro⁶⁰. However, they are constrained by limited cargo capacity, manufacturing complexity, and growing safety concerns including immunogenicity and insertional mutagenesis⁶⁰. In contrast, biomaterial-based nanoparticle systems are less efficient at stable gene modification and generally produce only transient expression, requiring highly potent engineered cells or repeat dosing. While this may be impractical for applications like solid tumors, which require sustained immune reprogramming to eliminate residual disease, it may be preferable in settings such as autoimmune reset to reduce risks associated with permanent genome modification and providing a built-in functional “off switch.” Furthermore, nanoparticle delivery systems offer major advantages in modularity, manufacturability, chemical tunability, cargo flexibility, and incorporation of immune-evasive or targeting functionalities. Accordingly, the optimal balance between durable and transient programming will likely depend on disease context, with cancer therapies often favoring persistence, whereas emerging evidence suggests some autoimmune diseases may respond effectively to a transient immune reset.^44,46

Bulk and injectable biomaterial platforms enable complementary strategies for in vivo immune engineering, but their differing modes of action create distinct trade-offs in spatial control, biological persistence, and translational feasibility. Bulk scaffolds can localize multiple biological cues within a spatially controlled synthetic niche, enabling recruitment, activation, or genetic modification of immune cells. This makes them particularly attractive for applications requiring coordinated multistep programming. However, their fixed implantation site, limited dose adjustability after administration, and greater manufacturing complexity may restrict their use. In contrast, injectable systems are more compatible with systemic administration, repeat dosing, and standardized manufacturing, making them more readily scalable for clinical use. However, they rely heavily on biodistribution, target-cell uptake, and transient intracellular delivery, thereby reducing spatial control and limiting the ability to coordinate multiple biological signals simultaneously.

These comparisons suggest that no single platform is optimal across all applications. Bulk scaffolds may be favored when local control and multi-signal programming are required, whereas nanoparticles may be preferable when scalable repeat dosing is prioritized. Durable viral systems may suit chronic disease settings, while transient nonviral approaches may be advantageous where reversibility and safety are paramount. What is increasingly clear, however, is that biomaterials uniquely enable forms of in vivo immune engineering that are difficult to achieve with conventional modalities alone.

In closing, biomaterials are rapidly redefining how immune therapies are designed, delivered, and ultimately realized in patients. What began as efforts to improve localization and delivery has evolved into a broader paradigm in which material properties, biological signaling, and immune dynamics are deliberately integrated to enable in vivo immune engineering. By coupling physical structure with biochemical instruction and, increasingly, genetic reprogramming, these platforms blur traditional boundaries between drugs, devices, and cell therapies. At the same time, their extensive capabilities introduce new challenges in predictability, dosing, and regulation that demand equally innovative evaluation frameworks. Continued progress will therefore depend not only on advances in material design, but also on deeper integration of immunology, systems biology, and regulatory science. Together, these efforts position biomaterial-enabled immune engineering as a foundational strategy for next-generation immunotherapies—one capable of transforming how complex cell-based treatments are manufactured, delivered, and ultimately scaled for broad clinical impact.

Table 2:

Summary of the major advancements

Biomaterial form	Biomaterial	Modification	Route	Function	Application	Ref
Scaffold	collagen	CXCL21, viral vector, a-CD3/CD28	Peritumoral	Recruitment, reprogramming, expansion	Solid tumors	20
Hydrogel	Alginate-collagen	Eliglustat, CXCL10 or CXCL11	Subcutaneous	Recruitment and reprogramming	inflammatory and autoimmune diseases.	21
Scaffold	Alginate	TGF-b, CXCL21, antibodies, IL2	Peritumoral	Recruitment, activation, Treg suppression	Solid tumors	22
Scaffold	PEG-based	Lentivirus	Peritumoral	Recruitment and reprogramming	Solid tumor	74
Hydrogel	Alginate	Axitinib, 4-1BB antibody, PF-06446846	Intratumoral/resection cavity	Reprogramming exhaustion	Solid tumor	29
Scaffold	Alginate	Retrovirus, IL2	Subcutaneous	Reprogramming and release	Solid tumor	23
Scaffold	self-assembling peptide FEFEFKFK	N/A	Peritumoral/intravenous	Reprogramming, release, expansion	Solid tumor	75
Scaffold	PLGA	a-CD3/CD28, IL7, IL15	Intratumoral injection	Stimulation and expansion	Solid tumors	25
Hydrogel	cationic polymer mPEG-PCL-PEI (PPP)	a-CD3e f(ab’)2 fragment and α-cyclodextrin (α-CD)	peritumoral	Transduction	Solid tumors	26
Hydrogel	Alginate	GM-CSF, CpG, doxorubicin-iRGD conjugate	peritumoral	Reprogramming TME	Solid tumors	30
Scaffold	Alginate	a-CD3/CD28, IL2, Retrovirus	Subcutaneous	Activation, reprogramming, release	Liquid tumors	32
Hydrogel	Alginate	a-CD3/CD28,	Subcutaneous	activation and expansion	Solid tumors	33
Scaffold	hyaluronic acid	a-CD3/CD28, IL2,	subcutaneous	Activation and expansion	Solid tumors	34
Scaffold	mesoporous silica rods	a-CD3/CD28	subcutaneous	CAR-T-cell expansion and differentiation	Liquid tumors	35
NPs	polymer	N/A	i.v.	reprogramming	Liquid and solid tumors	37
Nanovesicles	N/A	αCD3	i.v.	reprogramming	Liquid tumors	38
NPs	Lipid	a-CD3/CD28	i.v.	Activation and reprogramming	Liquid tumors	41
NPs	Lipid	αCD4	i.v	reprogramming	N/A	42
NPs	Lipid	αCD8	i.v.	reprogramming	Liquid tumors	43
NPs	Lipid	αCD7/CD3	i.v	reprogramming	Liquid tumors	44
NPs	Lipid	αCD8	i.v.	reprogramming	Autoimmune	45
NPs	Lipid	αCD5	i.v.	reprogramming	Cardiovascular disease	46
NPs	PLGA-PBAE	a-CD3/CD28, TGF-b	i.v.	reprogramming	Tolerogenic induction	47
NPs	DPNP	TORKinib PP242	i.v.	reprogramming	immune suppression	48
Cellbackpacks	protein nanogels	IL2	i.v.	modulation	Tolerogenic induction	50
Cellbackpacks	PHEA-g-CD/PBA/PEG block copolymers	HAase	i.v.	TME modulation	Solid tumors	51
NPs	PLGA	IL-2, Harmine	i.v.	modulation	tolerance induction	52

Key conclusions:

Instructive biomaterials address critical bottlenecks in conventional cell immunotherapies by enabling direct in vivo immune cell manipulation. By enabling precise, scalable, rapid and cost-effective cell modulation directly within patients, these platforms are positioned to broader and more durable clinical translation.

Breakthroughs discussed in the perspective:

This Perspective examines how instructive nanoparticle and bulk biomaterials are transforming T cell therapies in vivo. Moving beyond their traditional roles as cell reagents in vitro and passive carriers in vivo, biomaterials are now poised to reprogram and modulate immune cells directly within patients’ bodies. These platforms create programmable in situ immune niches that preserve cellular states and unlock new therapeutic potential in cancer and autoimmune diseases- beyond what is achievable through conventional ex vivo methods.

Future societal impact:

Current cell therapies are time-intensive, costly, and create significant accessibility barriers for patients. The current reliance on ex vivo culture methods not only imposes substantial economic and logistical burdens on healthcare systems but also compromises cell potency. Biomaterial-based approaches can fundamentally address these challenges by streamlining cell therapies – making them faster, more affordable and more scalable. These advances have the potential to reduce healthcare disparities, enable treatment in resource-limited settings, and transform advanced cell therapies from elite medical interventions available to few into broadly accessible treatments that benefit entire populations and reshape global health equity.

(1). The Bigger Picture.

Transformative cell therapies are rapidly expanding beyond cancer to treat autoimmune, infectious, and regenerative diseases. However, their widespread clinical adoption remains constrained by complex manufacturing workflows, logistical challenges, high treatment costs, and limited patient accessibility. Advances in biomaterials have enabled immune cell reprogramming directly within the body. By creating localized, instructive microenvironments, biomaterials can recruit, activate, genetically modify, support, and expand immune cells within their native tissue environments, reducing reliance on centralized manufacturing while providing precise spatial and temporal control over therapeutic responses. In this Perspective, we discuss how biomaterial platforms are reshaping the paradigm of cell manufacturing and delivery. We highlight the evolution of bulk and injectable biomaterials into multifunctional platforms capable of modulating immune cell activation, differentiation, and therapeutic function completely in vivo. We further examine how biomaterial properties and modifications regulate immune cell recruitment, activation, genetic engineering, persistence, and functional programming. Across bulk scaffolds, injectable matrices, and nanoparticles, we illustrate how engineered biomaterials can direct immune cell fate within the body, offering an alternative to conventional ex vivo manufacturing approaches. Finally, we discuss the opportunities and remaining challenges associated with translating these technologies into clinically viable therapies. Together, these advances highlight the potential of biomaterials to fundamentally transform how future cell therapies are engineered, manufactured, and delivered.

(2). Highlights.

• Biomaterials are redefining how therapeutic immune cells are engineered.

• Engineered biomaterials can precisely control immune cell fate and function in vivo or Biomaterials create synthetic niches for in vivo immune cell programming.

• Engineered biomaterials can streamline cell manufacturing or Biomaterial assisted cell programming has potential to replace complex manufacturing.

• Biomaterials can broaden access to next-generation cell therapies.

Data and Code Availability:

N/A