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Innovative Medicines & Omics Biocompatibility of nanomaterials

the reticuloendothelial system (RES), where they resist 5.1. Surface modifications
renal filtration and remain for prolonged durations. This Surface engineering plays a pivotal role in enhancing
sequestration may lead to oxidative damage, inflammation, nanomaterial biocompatibility. Among the most widely
or organ dysfunction. To address these issues, various adopted techniques is PEGylation, which involves attaching
5
strategies—such as PEGylation, encapsulation, or size PEG chains to the nanoparticle surface to minimize immune
reduction below 10 nm—have been developed to enhance detection and extend systemic circulation. 3,10,18 This “stealth”
clearance and mitigate RES uptake. 5 property allows therapeutic particles to circulate longer,
In contrast, biodegradable polymers such as polylactic increasing the likelihood of target site delivery.
acid (PLA) and polycaprolactone (PCL) degrade into Modifying surface properties such as charge,
biocompatible byproducts and offer greater safety for long- hydrophilicity, and the presence of targeting ligands also
term use. Yet, achieving consistent degradation rates across influences how nanomaterials interact with biological
30
various physiological environments remains challenging. components such as membranes, proteins, and cells. 11,18
Tailoring polymer composition and nanostructure These modifications help minimize protein corona
is essential to balance therapeutic performance with formation, reduce immunogenicity, and promote selective
predictable in vivo clearance. uptake by desired cell types. As will be explored later
with the CaO–CaP system, such tailoring becomes
4.3. Regulatory and safety concerns particularly important when adapting materials to specific
Regulatory pathways for nanomaterials often lag behind the physiological environments.
pace of technological advancement. Existing frameworks— Despite its advantages, PEGylation has limitations.
originally designed for bulk materials—fall short in addressing Repeated administration can result in accelerated
the unique risks posed by nanomaterials, particularly those clearance, and the immune system may develop anti-
related to long-term biodistribution, individual variability PEG antibodies. These concerns have prompted ongoing
in physiological responses, and complex immunological optimization efforts focusing on PEG chain density,
interactions. Agencies such as the FDA, EMA, and ISO have molecular weight, and branching to balance stealth effects
4
issued updated guidelines, but significant gaps remain in with immunological safety. 31
standardized testing protocols for nanomedicine.
Zwitterionic coatings present an alternative approach.
Developers are increasingly expected to adopt a safety- Composed of molecules carrying both positive and negative
by-design approach, including generating comprehensive charges—such as sulfobetaines and phosphorylcholines—
toxicology profiles and conducting lifecycle assessments these coatings form a densely hydrated shell that resists
during early-stage development. The need for harmonized protein adsorption. Debayle et al. demonstrated that
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global standards is especially urgent for nanotherapeutics zwitterionic polymers could completely inhibit corona
intended for systemic or repeat-dose administration. formation, outperforming PEGylation in maintaining
4,29
Bridging this regulatory gap requires multidisciplinary nanoparticle stealth and physiological stability.
collaboration and proactive engagement with policymakers. Another innovative approach leverages biomimicry.
5. Strategies for targeted improvement For example, by incorporating CD47 peptides onto
nanoparticle surfaces, researchers can mimic natural
To improve the clinical performance of nanomaterials, “do-not-eat-me” signals. These peptides engage the
targeted design strategies must be integrated early in the signal regulatory protein alpha receptor on macrophages,
development process. These strategies not only reduce suppressing phagocytosis and allowing for prolonged
adverse biological responses but also enhance the safety, circulation. However, caution is needed, as excessive
specificity, and real-world usability of nanomedical tools. immune suppression and potential blood-related toxicities
While many of these methods have proven successful in remain concerns in clinical settings. 33
controlled laboratory environments, translating them Another emerging strategy involves cloaking
into practical applications remains the true benchmark nanoparticles with cellular membranes—harvested from
of success. This section outlines four primary approaches: red blood cells, leukocytes, platelets, or cancer cells—to
surface engineering, biodegradable material selection, form biomimetic coatings. These membrane-derived
targeted delivery, and hybrid designs. Each strategy surfaces provide immune camouflaging and can even enable
offers a framework for enhancing biocompatibility and tissue-specific homing due to retained surface proteins
functionality. These concepts are further illustrated through and antigens. Such carriers have demonstrated promise
the case of the CaO–CaP binary system in Section 6. in drug delivery, detoxification, and vaccine delivery,

Volume 2 Issue 3 (2025) 49 doi: 10.36922/IMO025210024