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Lin et al. Cancer Drug Resist. 2026;9:14 Page 13 of 19

understanding and tools to quantify delivery-relevant phenomena in vivo . This consideration is
[79]
particularly important for PD-1/PD-L1-targeted combination nanotherapies, because delivery to the tumor
region does not necessarily ensure penetration into the tumor parenchyma or adequate exposure of the
immune and tumor cell subsets that the response to PD-1/PD-L1 blockade .
[79]

Immunogenicity and immune system interactions that can counteract benefit
For PD-1/PD-L1 nano-immunotherapy, delivery systems are not neutral containers. They can reshape
immune responses in ways that alter efficacy, safety, and the feasibility of repeated dosing. In PEGylated
systems, some individuals have pre-existing anti-PEG (polyethylene glycol) antibodies and that
PEG-modified compounds can induce additional anti-PEG antibodies. These antibodies can adversely affect
drug efficacy and safety, including through accelerated blood clearance .
[80]

Mechanistically, a study shows that anti-PEG antibodies can trigger complement activation on PEGylated
lipid-based NPs (including mRNA-LNPs). This process may compromise NP integrity and lead to premature
drug release or increased exposure of the cargo to serum proteins. The same study also reported correlations
between pre-existing anti-PEG IgM levels and complement activation in human donor plasma .
[81]

Beyond PEG, infusion-related hypersensitivity is increasingly recognized as a concern for LNPs. A review on
hypersensitivity to mRNA-LNP vaccines argues that rare anaphylaxis-like events resemble infusion reactions
previously observed with nanomedicines. It also emphasized the need for reliable predictive tools and safer
strategies for repeated administration, which are directly relevant to the design of nanocarriers intended for
repeated dosing alongside PD-1/PD-L1 therapy .
[82]

Safety, biodistribution, and toxicity risks in immune-oncology settings
For translational development, toxicity is not limited to the active payload. Nanomaterial composition,
production variables, route of administration, and tissue distribution patterns can all contribute to safety
liabilities. A recent article emphasizes that avoiding unacceptable toxicity with mRNA drugs and vaccines
remains challenging. It specifically discussed how cell tropism and tissue distribution of mRNA and LNPs
can lead to toxicity and reactogenicity, while also highlighted the limitations of current models for de-risking
off-target toxicity .
[83]

From a broader nanomedicine translation standpoint, the DELIVER framework in Caputo’s article explicitly
lists biocompatibility concerns and limited exposure at the target tissue and cell as critical barriers to clinical
success . These issues are particularly relevant to PD-1/PD-L1 strategies, because the therapeutic goal is to
[76]
improve antitumor immunity without provoking unacceptable systemic immune activation. Accordingly,
biodistribution and immune compatibility should be considered core design constraints rather than post hoc
concerns .
[83]

Bottlenecks in PD-1/PD-L1 clinical development
In the current PD-1/PD-L1 landscape, in which clinically effective monoclonal antibody therapies are already
well established, nanoformulations must demonstrate clear incremental value. This may include improving
intratumoral exposure in clinically relevant settings, enhancing the therapeutic index, or providing
measurable clinical benefit in the setting of resistance. At the same time, transparent and systematic safety
monitoring is essential to address risks jointly driven by both the payload and the carrier. Translational
frameworks further identify limited reproducibility in the pathway from preclinical studies to clinical

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